Comprehensive Physiology Wiley Online Library
For Librarians For Authors Editors About

Structure and Function of the Mammalian Neuromuscular Junction

Leah A. Davis, Matthew J. Fogarty, Alyssa Brown, Gary C. Sieck

10.1002/cphy.c210022

Source: Volume 12, Issue 4, October 2022

Published online: August 2022

Full Article on Wiley Online Library



Abstract

The mammalian neuromuscular junction (NMJ) comprises a presynaptic terminal, a postsynaptic receptor region on the muscle fiber (endplate), and the perisynaptic (terminal) Schwann cell. As with any synapse, the purpose of the NMJ is to transmit signals from the nervous system to muscle fibers. This neural control of muscle fibers is organized as motor units, which display distinct structural and functional phenotypes including differences in pre‐ and postsynaptic elements of NMJs. Motor units vary considerably in the frequency of their activation (both motor neuron discharge rate and duration/duty cycle), force generation, and susceptibility to fatigue. For earlier and more frequently recruited motor units, the structure and function of the activated NMJs must have high fidelity to ensure consistent activation and continued contractile response to sustain vital motor behaviors (e.g., breathing and postural balance). Similarly, for higher force less frequent behaviors (e.g., coughing and jumping), the structure and function of recruited NMJs must ensure short‐term reliable activation but not activation sustained for a prolonged period in which fatigue may occur. The NMJ is highly plastic, changing structurally and functionally throughout the life span from embryonic development to old age. The NMJ also changes under pathological conditions including acute and chronic disease. Such neuroplasticity often varies across motor unit types. © 2022 American Physiological Society. Compr Physiol 12: 3731–3766, 2022.

Figure 1. Figure 1. For a given level of glutamatergic input current (Isyn), the change in membrane potential (dVm/dt) will be greater for smaller motor neurons due to their lower membrane capacitance (size; Cm) and higher input resistance (Rin) compared to larger motor neurons. Thus, smaller motor neurons will reach the threshold for action potential generation sooner (i.e., earlier recruitment) than larger motor neurons. Smaller motor neurons also have smaller axons with slower action potential propagation velocities compared to larger motor neurons. These relationships constitute the Henneman's size principle for motor unit recruitment.
Figure 2. Figure 2. (A) Imaging of the phrenic motor neuron pool from rats acquired by confocal microscopy after labeling with tetramethylrhodamine‐dextran (nerve‐dip) or cholera toxin B (CTB) injected into the intrapleural space. Reused, with permission, from Mantilla CB, et al., 2009/ELSEVIER 279. (B) The distribution of phrenic motor neuron somal surface areas divided into tertiles. (C) Smaller motor neurons comprise slow (S; type I muscle fibers) and fast, fatigue‐resistant (FR; type IIa muscle fibers) motor units, whereas larger motor neurons comprise fast fatigue intermediate (FInt; type IIx muscle fibers) and fast fatigable (FF; type IIb muscle fibers). (D) In the rat diaphragm muscle (DIAm), a model predicting motor unit recruitment during different motor behaviors was developed based on (i) a recruitment order dependent on motor neuron size (S first FF last), (ii) the forces generated by each motor unit type, and (iii) the relative proportion of each motor unit type. The model predictions were compared to the transdiaphragmatic pressure (Pdi) or force generated by the DIAm 273. Based on this model, the lower Pdi generated during quiet breathing (eupnea) and hypercapnia/hypoxia stimulated breathing required the recruitment of only fatigue‐resistant S and FR motor units. In contrast, with more forceful (higher Pdi) DIAm efforts (e.g., coughing/sneezing and voiding) require recruitment of the entire phrenic motor neuron pool, including more fatigable FInt and FF motor units.
Figure 3. Figure 3. (A) Fiber‐type classification in the rat diaphragm muscle (DIAm) is based on immunoreactivity to primary antibodies for myosin heavy chain (MyHC) isoforms (pseudo‐colored in this example). Reused, with permission, from Mantilla CB, et al., 2010/ELSEVIER 273. (B) Composite table based on results from a number of studies displaying mean ± SD of muscle fiber cross‐sectional area, the proportion of fiber types within the DIAm, and specific force 273.
Figure 4. Figure 4. (A) An incoming motor neuron action potential is transduced to muscle fiber action potential, intracellular Ca2+ concentration ([Ca2+]i), and force response in a 1:1 ratio. At lower stimulus intensities, the [Ca2+]i and force responses do not summate, but as the frequency of activation increases, both the [Ca2+]i and force responses summate until they fuse. (B) In permeabilized muscle fibers, the relationship between [Ca2+] (pCa) and muscle force exhibits a sigmoidal relation that is shifted left in type I fibers compared with type II fibers 159. (C) The relationship between cat diaphragm muscle (DIAm) motor unit force and phrenic nerve stimulation frequency also displays a sigmoidal curve, which is shifted leftward for slow motor units as compared to fast motor units. Fast fatigue intermediate (FInt) and fast fatigable (FF) motor units display the most rightward shifted force‐frequency response curves 144,425. (D) Single motor unit action potentials or compound summated action potentials in the rat diaphragm muscle (DIAm) were recorded using electromyographic (EMG) electrodes. Single motor unit action potentials were identified by their constant waveform. In this example, the discharge profiles of three single motor units in the rat DIAm were discriminated. (E) Once recruited, the discharge rate of DIAm motor units increases as inspiratory efforts proceed. As inspiratory drive increases, the difference between onset and peak motor unit discharge rate increases, reflected frequency modulation of force generation to accomplish different behaviors 415.
Figure 5. Figure 5. (A) Pre‐ and postsynaptic elements of neuromuscular junctions (NMJs) on rat diaphragm muscle (DIAm) fibers can be visualized by confocal microscopy. Phrenic motor axon and presynaptic terminals were labeled by fluorescence immunostaining using neurofilamin antibody (red). Motor endplates were labeled using fluorescently tagged α‐bungarotoxin (green), which binds to cholinergic receptors. DIAm fiber types were distinguished by immunofluorescence using antibodies specific to different myosin heavy chain (MyHC) isoforms. In this example, immunoreactivity for anti‐MyHC2B was used. The MyHC2B isoform is co‐expressed with MyHC2X in rat DIAm fibers 159 so they are classified as type IIx/IIb. Accordingly, the two NMJs shown in this image are on type IIx/IIb DIAm fibers. (B) Electron micrographic (EM) image of a NMJ on a type IIx/IIb rat DIAm fiber in which it is possible to clearly distinguish the presynaptic terminal containing an active zone, synaptic vesicles, and the motor endplate containing junctional folds. Synaptic vesicles docked near the active zone hypothetically form a readily releasable pool, whereas non‐fused synaptic vesicles form a reserve pool. It is assumed that the availability of synaptic vesicles to fuse with the presynaptic terminal membrane near the active zone depends on the distance from the active zones.
Figure 6. Figure 6. (A) Postsynaptic responses to spontaneous or evoked synaptic vesicle release can be measured electrophysiologically. In this example, the response to the spontaneous exocytosis of ACh was observed as miniature endplate potentials (mEPPs) and more concerted release as evoked endplate potentials (EPPs) were recorded using an intracellular microelectrode in the muscle fiber. The microelectrode (glass micropipette) was inserted into a rat diaphragm muscle (DIAm) fiber near the neuromuscular junction identified by labeling the presynaptic terminal using FM4‐64. (B) Quantal content (QC determined as the ratio of EPP amplitude to mEPP amplitude) was significantly greater in type IIx/IIb DIAm fibers compared with type I and IIa fibers (*P < 0.01) 389. (C) In rat DIAm, the average mEPP amplitude recorded in type IIx/IIb fibers was significantly smaller than that in type I and IIa fibers (*P < 0.05) 389. (D) The frequency of spontaneous mEPPs was comparable among type I, IIa, and IIx/IIb fibers in the rat DIAm 389.
Figure 7. Figure 7. The SNARE protein complex mediates the docking and fusion of synaptic vesicles to the presynaptic terminal membrane. In response to a nerve action potential and depolarization of the presynaptic terminal, this process is initiated by the influx of Ca2+ (represented by the grey circles) via voltage‐gated Ca2+ channels. The elevated intracellular Ca2+ concentration ([Ca2+]i) leads to increased Ca2+ binding to synaptotagmin, which then triggers the signaling cascade responsible for synaptic vesicle fusion to the presynaptic terminal membrane near active zones. The SNARE signaling cascade involves synaptobrevin, mammalian uncoordinated‐18 (Munc18), complexin, and syntaxin working together to fuse the synaptic vesicle membrane to the presynaptic terminal membrane. Ca2+ channels are also tethered close to the synaptic vesicle by Munc13, rab3‐interacting molecules (RIM), and RIM binding protein (RIM‐BP).
Figure 8. Figure 8. (A) The average decline in quantal content (QC) over a 10‐min period of continuous 20‐Hz stimulation at type I or IIa vs type IIx/IIb fibers in the rat diaphragm muscle (DIAm). At both fiber types, there was a rapid early decline in QC (1st 100 s) followed by a slower (late) decline (beyond 300 s). Inset: Shows the immediate decline in QC occurring within the first 0.5 s. (B) The relative change in QC (normalized to the initial QC) is similar across type I or IIa and type IIx/IIb DIAm fibers in both the early and late phases of decline. However, there was a fiber type difference in the immediate decline in QC (<2.5 s; inset), with a greater relative change at type I or IIa fibers compared to that at type IIx/IIb fibers (P < 0.05). (C) The rate of synaptic vesicle replenishment from the reserve pool during repetitive phrenic nerve stimulation (20 or 50 Hz; 0.5 ms pulse duration) was estimated based on the difference between the predicted depletion of the readily‐ releasable pool of synaptic vesicles and the actual QC measurements at DIAm fibers. A higher rate of synaptic vesicle replenishment was observed at type IIx/IIb fibers compared to type I and IIa fibers (*P < 0.05). Figure used with permission from 389.
Figure 9. Figure 9. (A) Confocal imaging of presynaptic terminals at three different rat diaphragm muscle (DIAm) fibers labeled by the uptake of the styryl dye FM4‐64. (B) After loading the terminals with FM4‐64, the dye was washed from the bath and the terminals were destained by repetitive phrenic nerve stimulation at 10 Hz (0.5 ms supramaximal pulses with a 67% duty cycle for a 20‐min period) compared with presynaptic terminals at NMJs on type IIx/IIb fibers. Values are mean ± standard error for single‐exponential fitted curves.
Figure 10. Figure 10. FM4‐64 is applied extracellularly and is taken up into the presynaptic terminal through synaptic vesicle endocytosis. Confocal imaging during this initial process provides information on synaptic vesicle recycling. After loading the presynaptic terminal with FM4‐64, and rinsing the remaining extracellular FM4‐64, synaptic vesicle binding and release can be assessed by the decline in FM4‐64 fluorescence.
Figure 11. Figure 11. (A) Current traces from acetyl choline receptors (AChRs) at motor endplates of frog NMJs: (a) currents measured immediately above the AChR clusters and currents measured a short distance from the junctional folds at weaker (b) and stronger (c) stimulus pulses. Figures reproduced with permissions from 269. (B) The current‐voltage (I‐V) relationship for junctional (open) and extrajunctional (filled) AChRs at motor endplates of frog NMJs recorded using the patch‐clamp technique. The slope of I‐V relationship represents the conductance of the AChR channel. The reversal potential was 0 mV indicating the AChR at frog NMJs is a non‐selective cation channel.
Figure 12. Figure 12. (A) Averaged images from electron microscopy (EM) were used to reconstruct the nicotinic acetylcholine receptor (AChR) at 4.6 A resolution. The top right panel is the intracellular perspective, and the bottom right is extracellular 297. (B) AChRs are more densely clustered, typically at the peak of the junctional folds (red denotes greater density) compared with the troughs. Although this image is of a cultured rat myotube, which does not consistently exhibit junctional folds. Reproduced with copyright permissions from 452. (C) Agrin is released from the presynaptic cleft and binds to muscle‐specific kinase (MuSK) receptors on the muscle fiber. The binding of agrin to MuSK triggers an intracellular cascade that clusters the AChRs. Reproduced with copyright permissions from 308.
Figure 13. Figure 13. (A) Perinatal developmental timeline of the development of phrenic motor neurons and their innervation of muscle fibers in the rat diaphragm muscle (DIAm). (B) Photomicrographs of motor axons and presynaptic terminals labeled using an anti‐body specific for neurofilamin (green) and Schwann cells labeled using an anti‐body for S‐100. The merged image shows the close association of motor axons to Schwann cells. (C) During late embryonic and early postnatal development, DIAm fibers are innervated by more than one phrenic motor neuron (i.e., polyneuronal innervation). Subsequently, polyneuronal innervation disappears via synapse elimination leaving each muscle fiber innervated by only one motor axon.
Figure 14. Figure 14. In the rat diaphragm muscle (DIAm), quantal content (QC) decreases with repeated phrenic nerve stimulation (at 20 or 50 Hz; 0.5 ms pulse duration) in all fiber types (A. type I and IIa; B. type IIx/IIb) 389. A model of the replenishment of the readily releasable pool (RRP) of synaptic vesicles was developed to explain the initial decline of QC and the subsequent leveling of QC. For type I/IIa fibers, the initial decline in QC is steeper than can be explained by the depletion of the RRP, so at least part of this depletion was attributed to a decrease in the probability of synaptic vesicle release. For type IIx/IIb fibers the initial decline in QC was parallel to the depletion of the RRP, which suggests that the depletion is causal. All fiber types exhibit an ability to continuously release synaptic vesicles despite a continual decline in the RRP, therefore the sustained release is due to the repletion of synaptic vesicles through synaptic vesicle recycling. The probability of release and repletion of the RRP is difficult to directly measure so these remain suggested mechanisms, hence the question mark in the figure. The probability of release remains relatively unchanged at low compared to high frequencies for type I and IIa fibers. In contrast, higher frequencies substantially decrease the probability of release at type IIx/IIb DIAm fibers.
Figure 15. Figure 15. Neuromuscular transmission failure (NMTF) can occur due to failures at both the presynaptic and postsynaptic components of the neuromuscular junction (NMJ). At the presynaptic component, NMTF can be subdivided into branch point failure and a failure to release synaptic vesicles, which can be caused by either a decrease in the probability of release or depletion of the synaptic vesicle pools.
Figure 16. Figure 16. (A) One approach to test neuromuscular transmission failure (NMTF) is to repeatedly stimulate motor axons and compared the evoked forces to those evoked by intermittent direct muscle stimulation. NMTF is quantified as the difference between the amplitude of the forces evoked by direct muscle vs nerve stimulation. In the rat diaphragm muscle (DIAm), the extent of NMTF is dependent on the frequency of phrenic nerve stimulation such that at lower frequencies (B. 10 Hz) there is less divergence in the forces evoked by direct muscle versus nerve stimulation (i.e., less NMTF) than at higher frequencies (C. 75 Hz) 213.
Figure 17. Figure 17. Neurotrophin 4 (NT‐4) and brain‐derived neurotrophic factor (BDNF) are predominantly produced and released by motor neurons, although there is some evidence suggesting a myogenic pathway for these neurotrophins. Both NT‐4 and BDNF bind to a high affinity tropomyosin kinase B (TrkB) receptor located both pre‐ and postsynaptically. Some evidence suggests that TrkB and BDNF in the bound state are endocytosed and transported retrogradely via the axon to provide signaling to the soma. Republished, with permission, from Mantilla CB and Sieck GC, 2003 274.


Figure 1. For a given level of glutamatergic input current (Isyn), the change in membrane potential (dVm/dt) will be greater for smaller motor neurons due to their lower membrane capacitance (size; Cm) and higher input resistance (Rin) compared to larger motor neurons. Thus, smaller motor neurons will reach the threshold for action potential generation sooner (i.e., earlier recruitment) than larger motor neurons. Smaller motor neurons also have smaller axons with slower action potential propagation velocities compared to larger motor neurons. These relationships constitute the Henneman's size principle for motor unit recruitment.


Figure 2. (A) Imaging of the phrenic motor neuron pool from rats acquired by confocal microscopy after labeling with tetramethylrhodamine‐dextran (nerve‐dip) or cholera toxin B (CTB) injected into the intrapleural space. Reused, with permission, from Mantilla CB, et al., 2009/ELSEVIER 279. (B) The distribution of phrenic motor neuron somal surface areas divided into tertiles. (C) Smaller motor neurons comprise slow (S; type I muscle fibers) and fast, fatigue‐resistant (FR; type IIa muscle fibers) motor units, whereas larger motor neurons comprise fast fatigue intermediate (FInt; type IIx muscle fibers) and fast fatigable (FF; type IIb muscle fibers). (D) In the rat diaphragm muscle (DIAm), a model predicting motor unit recruitment during different motor behaviors was developed based on (i) a recruitment order dependent on motor neuron size (S first FF last), (ii) the forces generated by each motor unit type, and (iii) the relative proportion of each motor unit type. The model predictions were compared to the transdiaphragmatic pressure (Pdi) or force generated by the DIAm 273. Based on this model, the lower Pdi generated during quiet breathing (eupnea) and hypercapnia/hypoxia stimulated breathing required the recruitment of only fatigue‐resistant S and FR motor units. In contrast, with more forceful (higher Pdi) DIAm efforts (e.g., coughing/sneezing and voiding) require recruitment of the entire phrenic motor neuron pool, including more fatigable FInt and FF motor units.


Figure 3. (A) Fiber‐type classification in the rat diaphragm muscle (DIAm) is based on immunoreactivity to primary antibodies for myosin heavy chain (MyHC) isoforms (pseudo‐colored in this example). Reused, with permission, from Mantilla CB, et al., 2010/ELSEVIER 273. (B) Composite table based on results from a number of studies displaying mean ± SD of muscle fiber cross‐sectional area, the proportion of fiber types within the DIAm, and specific force 273.


Figure 4. (A) An incoming motor neuron action potential is transduced to muscle fiber action potential, intracellular Ca2+ concentration ([Ca2+]i), and force response in a 1:1 ratio. At lower stimulus intensities, the [Ca2+]i and force responses do not summate, but as the frequency of activation increases, both the [Ca2+]i and force responses summate until they fuse. (B) In permeabilized muscle fibers, the relationship between [Ca2+] (pCa) and muscle force exhibits a sigmoidal relation that is shifted left in type I fibers compared with type II fibers 159. (C) The relationship between cat diaphragm muscle (DIAm) motor unit force and phrenic nerve stimulation frequency also displays a sigmoidal curve, which is shifted leftward for slow motor units as compared to fast motor units. Fast fatigue intermediate (FInt) and fast fatigable (FF) motor units display the most rightward shifted force‐frequency response curves 144,425. (D) Single motor unit action potentials or compound summated action potentials in the rat diaphragm muscle (DIAm) were recorded using electromyographic (EMG) electrodes. Single motor unit action potentials were identified by their constant waveform. In this example, the discharge profiles of three single motor units in the rat DIAm were discriminated. (E) Once recruited, the discharge rate of DIAm motor units increases as inspiratory efforts proceed. As inspiratory drive increases, the difference between onset and peak motor unit discharge rate increases, reflected frequency modulation of force generation to accomplish different behaviors 415.


Figure 5. (A) Pre‐ and postsynaptic elements of neuromuscular junctions (NMJs) on rat diaphragm muscle (DIAm) fibers can be visualized by confocal microscopy. Phrenic motor axon and presynaptic terminals were labeled by fluorescence immunostaining using neurofilamin antibody (red). Motor endplates were labeled using fluorescently tagged α‐bungarotoxin (green), which binds to cholinergic receptors. DIAm fiber types were distinguished by immunofluorescence using antibodies specific to different myosin heavy chain (MyHC) isoforms. In this example, immunoreactivity for anti‐MyHC2B was used. The MyHC2B isoform is co‐expressed with MyHC2X in rat DIAm fibers 159 so they are classified as type IIx/IIb. Accordingly, the two NMJs shown in this image are on type IIx/IIb DIAm fibers. (B) Electron micrographic (EM) image of a NMJ on a type IIx/IIb rat DIAm fiber in which it is possible to clearly distinguish the presynaptic terminal containing an active zone, synaptic vesicles, and the motor endplate containing junctional folds. Synaptic vesicles docked near the active zone hypothetically form a readily releasable pool, whereas non‐fused synaptic vesicles form a reserve pool. It is assumed that the availability of synaptic vesicles to fuse with the presynaptic terminal membrane near the active zone depends on the distance from the active zones.


Figure 6. (A) Postsynaptic responses to spontaneous or evoked synaptic vesicle release can be measured electrophysiologically. In this example, the response to the spontaneous exocytosis of ACh was observed as miniature endplate potentials (mEPPs) and more concerted release as evoked endplate potentials (EPPs) were recorded using an intracellular microelectrode in the muscle fiber. The microelectrode (glass micropipette) was inserted into a rat diaphragm muscle (DIAm) fiber near the neuromuscular junction identified by labeling the presynaptic terminal using FM4‐64. (B) Quantal content (QC determined as the ratio of EPP amplitude to mEPP amplitude) was significantly greater in type IIx/IIb DIAm fibers compared with type I and IIa fibers (*P < 0.01) 389. (C) In rat DIAm, the average mEPP amplitude recorded in type IIx/IIb fibers was significantly smaller than that in type I and IIa fibers (*P < 0.05) 389. (D) The frequency of spontaneous mEPPs was comparable among type I, IIa, and IIx/IIb fibers in the rat DIAm 389.


Figure 7. The SNARE protein complex mediates the docking and fusion of synaptic vesicles to the presynaptic terminal membrane. In response to a nerve action potential and depolarization of the presynaptic terminal, this process is initiated by the influx of Ca2+ (represented by the grey circles) via voltage‐gated Ca2+ channels. The elevated intracellular Ca2+ concentration ([Ca2+]i) leads to increased Ca2+ binding to synaptotagmin, which then triggers the signaling cascade responsible for synaptic vesicle fusion to the presynaptic terminal membrane near active zones. The SNARE signaling cascade involves synaptobrevin, mammalian uncoordinated‐18 (Munc18), complexin, and syntaxin working together to fuse the synaptic vesicle membrane to the presynaptic terminal membrane. Ca2+ channels are also tethered close to the synaptic vesicle by Munc13, rab3‐interacting molecules (RIM), and RIM binding protein (RIM‐BP).


Figure 8. (A) The average decline in quantal content (QC) over a 10‐min period of continuous 20‐Hz stimulation at type I or IIa vs type IIx/IIb fibers in the rat diaphragm muscle (DIAm). At both fiber types, there was a rapid early decline in QC (1st 100 s) followed by a slower (late) decline (beyond 300 s). Inset: Shows the immediate decline in QC occurring within the first 0.5 s. (B) The relative change in QC (normalized to the initial QC) is similar across type I or IIa and type IIx/IIb DIAm fibers in both the early and late phases of decline. However, there was a fiber type difference in the immediate decline in QC (<2.5 s; inset), with a greater relative change at type I or IIa fibers compared to that at type IIx/IIb fibers (P < 0.05). (C) The rate of synaptic vesicle replenishment from the reserve pool during repetitive phrenic nerve stimulation (20 or 50 Hz; 0.5 ms pulse duration) was estimated based on the difference between the predicted depletion of the readily‐ releasable pool of synaptic vesicles and the actual QC measurements at DIAm fibers. A higher rate of synaptic vesicle replenishment was observed at type IIx/IIb fibers compared to type I and IIa fibers (*P < 0.05). Figure used with permission from 389.


Figure 9. (A) Confocal imaging of presynaptic terminals at three different rat diaphragm muscle (DIAm) fibers labeled by the uptake of the styryl dye FM4‐64. (B) After loading the terminals with FM4‐64, the dye was washed from the bath and the terminals were destained by repetitive phrenic nerve stimulation at 10 Hz (0.5 ms supramaximal pulses with a 67% duty cycle for a 20‐min period) compared with presynaptic terminals at NMJs on type IIx/IIb fibers. Values are mean ± standard error for single‐exponential fitted curves.


Figure 10. FM4‐64 is applied extracellularly and is taken up into the presynaptic terminal through synaptic vesicle endocytosis. Confocal imaging during this initial process provides information on synaptic vesicle recycling. After loading the presynaptic terminal with FM4‐64, and rinsing the remaining extracellular FM4‐64, synaptic vesicle binding and release can be assessed by the decline in FM4‐64 fluorescence.


Figure 11. (A) Current traces from acetyl choline receptors (AChRs) at motor endplates of frog NMJs: (a) currents measured immediately above the AChR clusters and currents measured a short distance from the junctional folds at weaker (b) and stronger (c) stimulus pulses. Figures reproduced with permissions from 269. (B) The current‐voltage (I‐V) relationship for junctional (open) and extrajunctional (filled) AChRs at motor endplates of frog NMJs recorded using the patch‐clamp technique. The slope of I‐V relationship represents the conductance of the AChR channel. The reversal potential was 0 mV indicating the AChR at frog NMJs is a non‐selective cation channel.


Figure 12. (A) Averaged images from electron microscopy (EM) were used to reconstruct the nicotinic acetylcholine receptor (AChR) at 4.6 A resolution. The top right panel is the intracellular perspective, and the bottom right is extracellular 297. (B) AChRs are more densely clustered, typically at the peak of the junctional folds (red denotes greater density) compared with the troughs. Although this image is of a cultured rat myotube, which does not consistently exhibit junctional folds. Reproduced with copyright permissions from 452. (C) Agrin is released from the presynaptic cleft and binds to muscle‐specific kinase (MuSK) receptors on the muscle fiber. The binding of agrin to MuSK triggers an intracellular cascade that clusters the AChRs. Reproduced with copyright permissions from 308.


Figure 13. (A) Perinatal developmental timeline of the development of phrenic motor neurons and their innervation of muscle fibers in the rat diaphragm muscle (DIAm). (B) Photomicrographs of motor axons and presynaptic terminals labeled using an anti‐body specific for neurofilamin (green) and Schwann cells labeled using an anti‐body for S‐100. The merged image shows the close association of motor axons to Schwann cells. (C) During late embryonic and early postnatal development, DIAm fibers are innervated by more than one phrenic motor neuron (i.e., polyneuronal innervation). Subsequently, polyneuronal innervation disappears via synapse elimination leaving each muscle fiber innervated by only one motor axon.


Figure 14. In the rat diaphragm muscle (DIAm), quantal content (QC) decreases with repeated phrenic nerve stimulation (at 20 or 50 Hz; 0.5 ms pulse duration) in all fiber types (A. type I and IIa; B. type IIx/IIb) 389. A model of the replenishment of the readily releasable pool (RRP) of synaptic vesicles was developed to explain the initial decline of QC and the subsequent leveling of QC. For type I/IIa fibers, the initial decline in QC is steeper than can be explained by the depletion of the RRP, so at least part of this depletion was attributed to a decrease in the probability of synaptic vesicle release. For type IIx/IIb fibers the initial decline in QC was parallel to the depletion of the RRP, which suggests that the depletion is causal. All fiber types exhibit an ability to continuously release synaptic vesicles despite a continual decline in the RRP, therefore the sustained release is due to the repletion of synaptic vesicles through synaptic vesicle recycling. The probability of release and repletion of the RRP is difficult to directly measure so these remain suggested mechanisms, hence the question mark in the figure. The probability of release remains relatively unchanged at low compared to high frequencies for type I and IIa fibers. In contrast, higher frequencies substantially decrease the probability of release at type IIx/IIb DIAm fibers.


Figure 15. Neuromuscular transmission failure (NMTF) can occur due to failures at both the presynaptic and postsynaptic components of the neuromuscular junction (NMJ). At the presynaptic component, NMTF can be subdivided into branch point failure and a failure to release synaptic vesicles, which can be caused by either a decrease in the probability of release or depletion of the synaptic vesicle pools.


Figure 16. (A) One approach to test neuromuscular transmission failure (NMTF) is to repeatedly stimulate motor axons and compared the evoked forces to those evoked by intermittent direct muscle stimulation. NMTF is quantified as the difference between the amplitude of the forces evoked by direct muscle vs nerve stimulation. In the rat diaphragm muscle (DIAm), the extent of NMTF is dependent on the frequency of phrenic nerve stimulation such that at lower frequencies (B. 10 Hz) there is less divergence in the forces evoked by direct muscle versus nerve stimulation (i.e., less NMTF) than at higher frequencies (C. 75 Hz) 213.


Figure 17. Neurotrophin 4 (NT‐4) and brain‐derived neurotrophic factor (BDNF) are predominantly produced and released by motor neurons, although there is some evidence suggesting a myogenic pathway for these neurotrophins. Both NT‐4 and BDNF bind to a high affinity tropomyosin kinase B (TrkB) receptor located both pre‐ and postsynaptically. Some evidence suggests that TrkB and BDNF in the bound state are endocytosed and transported retrogradely via the axon to provide signaling to the soma. Republished, with permission, from Mantilla CB and Sieck GC, 2003 274.
References
 1.Ackermann F, Waites CL, Garner CC. Presynaptic active zones in invertebrates and vertebrates. EMBO Rep 16: 923‐938, 2015.
 2.Adelman WJ, Palti Y, Senft JP. Potassium ion accumulation in a periaxonal space and its effect on the measurement of membrane potassium ion conductance. J Membr Biol 13: 387‐410, 1973.
 3.Albuquerque EX, Barnard EA, Porter CW, Warnick JE. The density of acetylcholine receptors and their sensitivity in the postsynaptic membrane of muscle endplates. Proc Natl Acad Sci U S A 71: 2818‐2822, 1974.
 4.Aldrich TK, Shander A, Chaudhry I, Nagashima H. Fatigue of isolated rat diaphragm: Role of impaired neuromuscular transmission. J Appl Physiol 61 (3): 1077‐1083, 1986.
 5.Alhindi A, Boehm I, Chaytow H. Small junction, big problems: Neuromuscular junction pathology in mouse models of amyotrophic lateral sclerosis (ALS). J Anat, 2021. DOI: 10.1111/joa.13463.
 6.Allan DW, Greer JJ. Embryogenesis of the phrenic nerve and diaphragm in the fetal rat. J Comp Neurol 382: 459‐468, 1997.
 7.Allodi I, Comley L, Nichterwitz S, Nizzardo M, Simone C, Benitez JA, Cao M, Corti S, Hedlund E. Differential neuronal vulnerability identifies IGF‐2 as a protective factor in ALS. Sci Rep 6: 25960, 2016.
 8.Alshekhlee A, Miles JD, Katirji B, Preston DC, Kaminski HJ. Incidence and mortality rates of myasthenia gravis and myasthenic crisis in US hospitals. Neurology 72: 1548‐1554, 2009.
 9.Arbour D, Tremblay E, Martineau E, Julien JP, Robitaille R. Early and persistent abnormal decoding by glial cells at the neuromuscular junction in an ALS model. J Neurosci 35: 688‐706, 2015.
 10.Ariyasu RG, Deerinck TJ, Levinson SR, Ellisman MH. Distribution of (Na+ + K+)ATPase and sodium channels in skeletal muscle and electroplax. J Neurocytol 16: 511‐522, 1987.
 11.Arthur‐Farraj PJ, Latouche M, Wilton DK, Quintes S, Chabrol E, Banerjee A, Woodhoo A, Jenkins B, Rahman M, Turmaine M, Wicher GK, Mitter R, Greensmith L, Behrens A, Raivich G, Mirsky R, Jessen KR. c‐Jun reprograms Schwann cells of injured nerves to generate a repair cell essential for regeneration. Neuron 75: 633‐647, 2012.
 12.Asbury AK. Schwann cell proliferation in developing mouse sciatic nerve. A radioautographic study. J Cell Biol 34: 735‐743, 1967.
 13.Aubier M, Viires N. Calcium ATPase and respiratory muscle function. Eur Respir J 11: 758‐766, 1998.
 14.Auerbach A, Akk G. Desensitization of mouse nicotinic acetylcholine receptor channels. A two‐gate mechanism. J Gen Physiol 112: 181‐197, 1998.
 15.Auld DS, Robitaille R. Perisynaptic Schwann cells at the neuromuscular junction: Nerve‐ and activity‐dependent contributions to synaptic efficacy, plasticity, and reinnervation. Neuroscientist 9: 144‐157, 2003.
 16.Azarias G, Kruusmagi M, Connor S, Akkuratov EE, Liu XL, Lyons D, Brismar H, Broberger C, Aperia A. A specific and essential role for Na, K‐ATPase alpha3 in neurons co‐expressing alpha1 and alpha3. J Biol Chem 288: 2734‐2743, 2013.
 17.Bacskai T, Fu Y, Sengul G, Rusznak Z, Paxinos G, Watson C. Musculotopic organization of the motor neurons supplying forelimb and shoulder girdle muscles in the mouse. Brain Struct Funct 218: 221‐238, 2013.
 18.Bacskai T, Rusznak Z, Paxinos G, Watson C. Musculotopic organization of the motor neurons supplying the mouse hindlimb muscles: A quantitative study using Fluoro‐Gold retrograde tracing. Brain Struct Funct 219: 303‐321, 2014.
 19.Balaji J, Ryan TA. Single‐vesicle imaging reveals that synaptic vesicle exocytosis and endocytosis are coupled by a single stochastic mode. Proc Natl Acad Sci U S A 104: 20576‐20581, 2007.
 20.Balice‐Gordon RJ, Lichtman JW. In vivo visualization of the growth of pre‐ and postsynaptic elements of neuromuscular junctions in the mouse. J Neurosci 10: 894‐908, 1990.
 21.Balice‐Gordon RJ, Lichtman JW. In vivo observations of pre‐ and postsynaptic changes during the transition from multiple to single innervation at developing neuromuscular junctions. J Neurosci 13: 834‐855, 1993.
 22.Baloh RH, Strickland A, Ryu E, Le N, Fahrner T, Yang M, Nagarajan R, Milbrandt J. Congenital hypomyelinating neuropathy with lethal conduction failure in mice carrying the Egr2 I268N mutation. J Neurosci 29: 2312‐2321, 2009.
 23.Bamji SX, Majdan M, Pozniak CD, Belliveau DJ, Aloyz R, Kohn J, Causing CG, Miller FD. The p75 neurotrophin receptor mediates neuronal apoptosis and is essential for naturally occurring sympathetic neuron death. J Cell Biol 140: 911‐923, 1998.
 24.Bandi E, Jevsek M, Mars T, Jurdana M, Formaggio E, Sciancalepore M, Fumagalli G, Grubic Z, Ruzzier F, Lorenzon P. Neural agrin controls maturation of the excitation‐contraction coupling mechanism in human myotubes developing in vitro. Am J Physiol Cell Physiol 294: C66‐C73, 2008.
 25.Banker BQ, Kelly SS, Robbins N. Neuromuscular transmission and correlative morphology in young and old mice. J Physiol 339: 355‐377, 1983.
 26.Banks GB, Choy PT, Lavidis NA, Noakes PG. Neuromuscular synapses mediate motor axon branching and motoneuron survival during the embryonic period of programmed cell death. Dev Biol 257: 71‐84, 2003.
 27.Banks GB, Kanjhan R, Wiese S, Kneussel M, Wong LM, O'Sullivan G, Sendtner M, Bellingham MC, Betz H, Noakes PG. Glycinergic and GABAergic synaptic activity differentially regulate motoneuron survival and skeletal muscle innervation. [Erratum appears in J Neurosci. 2005 Mar 16; 25 (11): 3018‐21]. J Neurosci 25: 1249‐1259, 2005.
 28.Baraka A. Nerve and muscle stimulation of the rat isolated phrenic nerve‐ diaphragm preparation. Anesth Analg 53: 594‐596, 1974.
 29.Barber MJ, Lichtman JW. Activity‐driven synapse elimination leads paradoxically to domination by inactive neurons. J Neurosci 19: 9975‐9985, 1999.
 30.Barrett EF, Barrett JN, David G. Mitochondria in motor nerve terminals: Function in health and in mutant superoxide dismutase 1 mouse models of familial ALS. J Bioenerg Biomembr 43: 581‐586, 2011.
 31.Barrett EF, Barrett JN, David G. Dysfunctional mitochondrial Ca(2+) handling in mutant SOD1 mouse models of fALS: Integration of findings from motor neuron somata and motor terminals. Front Cell Neurosci 8: 184, 2014.
 32.Barrett GL. The p75 neurotrophin receptor and neuronal apoptosis. Prog Neurobiol 61: 205‐229, 2000.
 33.Bazzy AR, Donnelly DF. Failure to generate action potentials in newborn diaphragms following nerve stimulation. Brain Res 600: 349‐352, 1993.
 34.Bennett MK, Calakos N, Scheller RH. Syntaxin: A synaptic protein implicated in docking of synaptic vesicles at presynaptic active zones. Science 257: 255‐259, 1992.
 35.Bennett MR, Lavidis NA. Segmental motor projections to rat muscles during the loss of polyneuronal innervation. Dev Brain Res 13: 1‐7, 1984.
 36.Bennett MR, Pettigrew AG. The formation of synapses in striated muscle during development. J Physiol 241: 515‐545, 1974.
 37.Betz WJ, Bewick GS, Ridge RM. Intracellular movements of fluorescently labeled synaptic vesicles in frog motor nerve terminals during nerve stimulation. Neuron 9: 805‐813, 1992.
 38.Betz WJ, Caldwell JH, Ribchester RR. The size of motor units during post‐natal development of rat lumbrical muscle. J Physiol 297: 463‐478, 1979.
 39.Betz WJ, Caldwell JH, Ribchester RR. The effects of partial denervation at birth on the development of muscle fibres and motor units in rat lumbrical muscle. J Physiol 303: 265‐279, 1980.
 40.Betz WJ, Mao F, Bewick GS. Activity‐dependent fluorescent staining and destaining of living vertebrate motor nerve terminals. J Neurosci 12: 363‐375, 1992.
 41.Betz WJ, Ribchester RR, Ridge RM. Competitive mechanisms underlying synapse elimination in the lumbrical muscle of the rat. J Neurobiol 21: 1‐17, 1990.
 42.Bishop DL, Misgeld T, Walsh MK, Gan WB, Lichtman JW. Axon branch removal at developing synapses by axosome shedding. Neuron 44: 651‐661, 2004.
 43.Bjornskov EK, Norris FH Jr, Mower‐Kuby J. Quantitative axon terminal and end‐plate morphology in amyotrophic lateral sclerosis. Arch Neurol 41: 527‐530, 1984.
 44.Blakely RD, Edwards RH. Vesicular and plasma membrane transporters for neurotransmitters. Cold Spring Harb Perspect Biol 4: a005595, 2012.
 45.Blanco CE, Zhan WZ, Fang YH, Sieck GC. Exogenous testosterone treatment decreases diaphragm neuromuscular transmission failure in male rats. J Appl Physiol 90: 850‐856, 2001.
 46.Blanco G, Mercer RW. Isozymes of the Na‐K‐ATPase: Heterogeneity in structure, diversity in function. Am J Phys 275: F633‐F650, 1998.
 47.Bockmann RA, Grubmuller H. Multistep binding of divalent cations to phospholipid bilayers: A molecular dynamics study. Angew Chem Int Ed Engl 43: 1021‐1024, 2004.
 48.Bodine SC, Roy RR, Eldred E, Edgerton VR. Maximal force as a function of anatomical features of motor units in the cat tibialis anterior. J Neurophysiol 57 (6): 1730‐1745, 1987.
 49.Boehm I, Alhindi A, Leite AS, Logie C, Gibbs A, Murray O, Farrukh R, Pirie R, Proudfoot C, Clutton R, Wishart TM, Jones RA, Gillingwater TH. Comparative anatomy of the mammalian neuromuscular junction. J Anat 237: 827‐836, 2020.
 50.Boncompagni S, Protasi F, Franzini‐Armstrong C. Sequential stages in the age‐dependent gradual formation and accumulation of tubular aggregates in fast twitch muscle fibers: SERCA and calsequestrin involvement. Age (Dordr) 34: 27‐41, 2012.
 51.Bottger P, Tracz Z, Heuck A, Nissen P, Romero‐Ramos M, Lykke‐Hartmann K. Distribution of Na/K‐ATPase alpha 3 isoform, a sodium‐potassium P‐type pump associated with rapid‐onset of dystonia parkinsonism (RDP) in the adult mouse brain. J Comp Neurol 519: 376‐404, 2011.
 52.Bourque MJ, Robitaille R. Endogenous peptidergic modulation of perisynaptic Schwann cells at the frog neuromuscular junction. J Physiol 512 (Pt 1): 197‐209, 1998.
 53.Boyd IA, Martin AR. Spontaneous subthreshold activity at mammalian neural muscular junctions. J Physiol 132: 61‐73, 1956.
 54.Brandenburg JE, Fogarty MJ, Brown AD, Sieck GC. Phrenic motor neuron loss in an animal model of early onset hypertonia. J Neurophysiol 123: 1682‐1690, 2020.
 55.Brandenburg JE, Gransee HM, Fogarty MJ, Sieck GC. Differences in lumbar motor neuron pruning in an animal model of early onset spasticity. J Neurophysiol 120: 601‐609, 2018.
 56.Braun T, Bober E, Buschhausen‐Denker G, Kohtz S, Grzeschik KH, Arnold HH, Kotz S. Differential expression of myogenic determination genes in muscle cells: Possible autoactivation by the Myf gene products. EMBO J 8: 3617‐3625, 1989.
 57.Braun T, Buschhausen‐Denker G, Bober E, Tannich E, Arnold HH. A novel human muscle factor related to but distinct from MyoD1 induces myogenic conversion in 10T1/2 fibroblasts. EMBO J 8: 701‐709, 1989.
 58.Brockhausen J, Cole RN, Gervasio OL, Ngo ST, Noakes PG, Phillips WD. Neural agrin increases postsynaptic ACh receptor packing by elevating rapsyn protein at the mouse neuromuscular synapse. Dev Neurobiol 68: 1153‐1169, 2008.
 59.Brody IA, Engel WK. Denervation of muscle in myasthenia gravis. Report of a patient with myasthenia gravis for 47 years and histochemical signs of denervation. Arch Neurol 11: 350‐354, 1964.
 60.Brose N, Petrenko AG, Sudhof TC, Jahn R. Synaptotagmin: A calcium sensor on the synaptic vesicle surface. Science 256: 1021‐1025, 1992.
 61.Brown MC, Jansen JKS, Van Essen D. Polyneuronal innervation of skeletal muscle in new‐born rats and its elimination during maturation. J Physiol 261: 387‐422, 1976.
 62.Bruneteau G, Bauche S, Gonzalez de Aguilar JL, Brochier G, Mandjee N, Tanguy ML, Hussain G, Behin A, Khiami F, Sariali E, Hell‐Remy C, Salachas F, Pradat PF, Lacomblez L, Nicole S, Fontaine B, Fardeau M, Loeffler JP, Meininger V, Fournier E, Koenig J, Hantai D. Endplate denervation correlates with Nogo‐A muscle expression in amyotrophic lateral sclerosis patients. Ann Clin Transl Neurol 2: 362‐372, 2015.
 63.Buffelli M, Busetto G, Cangiano L, Cangiano A. Perinatal switch from synchronous to asynchronous activity of motoneurons: Link with synapse elimination. Proc Natl Acad Sci U S A 99: 13200‐13205, 2002.
 64.Buffelli M, Tognana E, Cangiano A, Busetto G. Activity‐dependent vs. neurotrophic modulation of acetylcholine receptor expression: Evidence from rat soleus and extensor digitorum longus muscles confirms the exclusive role of activity. Eur J Neurosci 47: 1474‐1481, 2018.
 65.Burke RE, Levine DN, Tsairis P, Zajac FE 3rd. Physiological types and histochemical profiles in motor units of the cat gastrocnemius. J Physiol 234: 723‐748, 1973.
 66.Burres SA, Crayton JW, Gomez CM, Richman DP. Myasthenia induced by monoclonal anti‐acetylcholine receptor antibodies: Clinical and electrophysiological aspects. Ann Neurol 9: 563‐568, 1981.
 67.Butler JE, McKenzie DK, Gandevia SC. Discharge properties and recruitment of human diaphragmatic motor units during voluntary inspiratory tasks. J Physiol 518 (Pt 3): 907‐920, 1999.
 68.Caldwell JH. Clustering of sodium channels at the neuromuscular junction. Microsc Res Tech 49: 84‐89, 2000.
 69.Cantor S, Zhang W, Delestree N, Remedio L, Mentis GZ, Burden SJ. Preserving neuromuscular synapses in ALS by stimulating MuSK with a therapeutic agonist antibody. elife 7: e34375, 2018.
 70.Cappello V, Vezzoli E, Righi M, Fossati M, Mariotti R, Crespi A, Patruno M, Bentivoglio M, Pietrini G, Francolini M. Analysis of neuromuscular junctions and effects of anabolic steroid administration in the SOD1G93A mouse model of ALS. Mol Cell Neurosci 51: 12‐21, 2012.
 71.Ceci ML, Mardones‐Krsulovic C, Sanchez M, Valdivia LE, Allende ML. Axon‐Schwann cell interactions during peripheral nerve regeneration in zebrafish larvae. Neural Dev 9: 22, 2014.
 72.Chand KK, Lee KM, Lee JD, Qiu H, Willis EF, Lavidis NA, Hilliard MA, Noakes PG. Defects in synaptic transmission at the neuromuscular junction precede motor deficits in a TDP‐43(Q331K) transgenic mouse model of amyotrophic lateral sclerosis. FASEB J 32: 2676‐2689, 2018.
 73.Changeux JP, Kasai M, Lee CY. Use of a snake venom toxin to characterize the cholinergic receptor protein. Proc Natl Acad Sci U S A 67: 1241‐1247, 1970.
 74.Chen J, Mizushige T, Nishimune H. Active zone density is conserved during synaptic growth but impaired in aged mice. J Comp Neurol 520: 434‐452, 2012.
 75.Cheng AJ, Allodi I, Chaillou T, Schlittler M, Ivarsson N, Lanner JT, Thams S, Hedlund E, Andersson DC. Intact single muscle fibres from SOD1(G93A) amyotrophic lateral sclerosis mice display preserved specific force, fatigue resistance and training‐like adaptations. J Physiol 597: 3133‐3146, 2019.
 76.Chipman PH, Schachner M, Rafuse VF. Presynaptic NCAM is required for motor neurons to functionally expand their peripheral field of innervation in partially denervated muscles. J Neurosci 34: 10497‐10510, 2014.
 77.Clark JA, Southam KA, Blizzard CA, King AE, Dickson TC. Axonal degeneration, distal collateral branching and neuromuscular junction architecture alterations occur prior to symptom onset in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis. J Chem Neuroanat 76: 35‐47, 2016.
 78.Clemence A, Mirsky R, Jessen KR. Non‐myelin‐forming Schwann cells proliferate rapidly during Wallerian degeneration in the rat sciatic nerve. J Neurocytol 18: 185‐192, 1989.
 79.Coers C, Telerman‐Toppet N. Morphological and histochemical changes of motor units in myasthenia. Ann N Y Acad Sci 274: 6‐19, 1976.
 80.Coers C, Telerman‐Toppet N, Gerard JM, Szliwowski H, Bethlem J, van Wijngaarden GK. Changes in motor innervation and histochemical pattern of muscle fibers in some congenital myopathies. Neurology 26: 1046‐1053, 1976.
 81.Cohen I, Kita H, Van Der Kloot W. The Intervals Between Miniature End‐plate Potentials in the Frog are Unlikely to be independently or exponentially distributed. J Physiol 236: 327‐339, 1974.
 82.Cole RN, Ghazanfari N, Ngo ST, Gervasio OL, Reddel SW, Phillips WD. Patient autoantibodies deplete postsynaptic muscle‐specific kinase leading to disassembly of the ACh receptor scaffold and myasthenia gravis in mice. J Physiol 588: 3217‐3229, 2010.
 83.Cole RN, Reddel SW, Gervasio OL, Phillips WD. Anti‐MuSK patient antibodies disrupt the mouse neuromuscular junction. Ann Neurol 63: 782‐789, 2008.
 84.Courtney J, Steinbach JH. Age changes in neuromucular junction morphology and acetylcholine receptor distribution on rat skeletal muscle fibres. J Physiol 320: 435‐447, 1981.
 85.Crambert G, Hasler U, Beggah AT, Yu C, Modyanov NN, Horisberger JD, Lelievre L, Geering K. Transport and pharmacological properties of nine different human Na, K‐ATPase isozymes. J Biol Chem 275: 1976‐1986, 2000.
 86.Cull‐Candy SG, Miledi R, Trautmann A, Uchitel OD. On the release of transmitter at normal, myasthenia gravis and myasthenic syndrome affected human end‐plates. J Physiol 299: 621‐638, 1980.
 87.Dahm LM, Landmesser LT. The regulation of synaptogenesis during normal development and following activity blockade. J Neurosci 11: 238‐255, 1991.
 88.David G, Barrett EF. Stimulation‐evoked increases in cytosolic [Ca(2+)] in mouse motor nerve terminals are limited by mitochondrial uptake and are temperature‐dependent. J Neurosci 20: 7290‐7296, 2000.
 89.David G, Barrett EF. Mitochondrial Ca2+ uptake prevents desynchronization of quantal release and minimizes depletion during repetitive stimulation of mouse motor nerve terminals. J Physiol 548: 425‐438, 2003.
 90.Davis RL, Weintraub H, Lassar B. Expression of a single transfected cDNA converts fibrobalsts to myoblasts. Cell 51: 987‐1000, 1987.
 91.de Carvalho M, Swash M. Nerve conduction studies in amyotrophic lateral sclerosis. Muscle Nerve 23: 344‐352, 2000.
 92.De Robertis ED, Bennett HS. Some features of the submicroscopic morphology of synapses in frog and earthworm. J Biophys Biochem Cytol 1: 47‐58, 1955.
 93.del Castillo J, Katz B. Quantal components of the end‐plate potential. J Physiol 124: 560‐573, 1954.
 94.Denker A, Rizzoli SO. Synaptic vesicle pools: An update. Front Synaptic Neurosci 2: 135, 2010.
 95.Dennis MJ, Ziskind‐Conhaim L, Harris AJ. Development of neuromuscular junctions in rat embryos. Dev Biol 81: 266‐279, 1981.
 96.Desaphy JF, De Luca A, Imbrici P, Conte CD. Modification by ageing of the tetrodotoxin‐sensitive sodium channels in rat skeletal muscle fibres. Biochim Biophys Acta 1373: 37‐46, 1998.
 97.Dionne VE, Leibowitz MD. Acetylcholine receptor kinetics. A description from single‐channel currents at snake neuromuscular junctions. Biophys J 39: 253‐261, 1982.
 98.Donaldson IM. Robert Hooke's Micrographia of 1665 and 1667. J R Coll Physicians Edinb 40: 374‐376, 2010.
 99.Duchen MR. Ca(2+)‐dependent changes in the mitochondrial energetics in single dissociated mouse sensory neurons. Biochem J 283 (Pt 1): 41‐50, 1992.
 100.Dukkipati SS, Garrett TL, Elbasiouny SM. The vulnerability of spinal motoneurons and soma size plasticity in a mouse model of amyotrophic lateral sclerosis. J Physiol 596: 1723‐1745, 2018.
 101.Dupuis L, Pehar M, Cassina P, Rene F, Castellanos R, Rouaux C, Gandelman M, Dimou L, Schwab ME, Loeffler JP, Barbeito L, Gonzalez de Aguilar JL. Nogo receptor antagonizes p75NTR‐dependent motor neuron death. Proc Natl Acad Sci U S A 105: 740‐745, 2008.
 102.Duxson MJ, Ross JJ, Harris AJ. Transfer of differentiated synaptic terminals from primary myotubes to new‐formed muscle cells during embryonic development in the rat. Neurosci Lett 71: 147‐152, 1986.
 103.Eccles JCK, B; Kuffler S.W. Nature of the “endplate potential” in curarized muscle. J Neurophysiol 4: 362‐387, 1941.
 104.Edstrom L, Kugelberg E. Histochemical composition, distribution of fibres and fatiguability of single motor units. Anterior tibial muscle of the rat. J Neurol Neurosurg Psychiatry 31: 424‐433, 1968.
 105.Edwards IJ, Bruce G, Lawrenson C, Howe L, Clapcote SJ, Deuchars SA, Deuchars J. Na+/K+ ATPase alpha1 and alpha3 isoforms are differentially expressed in alpha‐ and gamma‐motoneurons. J Neurosci 33: 9913‐9919, 2013.
 106.Ellis DZ, Rabe J, Sweadner KJ. Global loss of Na, K‐ATPase and its nitric oxide‐mediated regulation in a transgenic mouse model of amyotrophic lateral sclerosis. J Neurosci 23: 43‐51, 2003.
 107.Enad JG, Fournier M, Sieck GC. Oxidative capacity and capillary density of diaphragm motor units. J Appl Physiol 67: 620‐627, 1989.
 108.Engel AG, Lindstrom JM, Lambert EH, Lennon VA. Ultrastructural localization of the acetylcholine receptor in myasthenia gravis and in its experimental autoimmune model. Neurology 27: 307‐315, 1977.
 109.Engel AG, Nagel A, Walls TJ, Harper CM, Waisburg HA. Congenital myasthenic syndromes: I. Deficiency and short open‐time of the acetylcholine receptor. Muscle Nerve 16: 1284‐1292, 1993.
 110.Engel AG, Shen XM, Selcen D, Sine SM. Congenital myasthenic syndromes: Pathogenesis, diagnosis, and treatment. Lancet Neurol 14: 461, 2015.
 111.Engel AG, Tsujihata M, Lambert EH, Lindstrom JM, Lennon VA. Experimental autoimmune myasthenia gravis: A sequential and quantitative study of the neuromuscular junction ultrastructure and electrophysiologic correlations. J Neuropathol Exp Neurol 35: 569‐587, 1976.
 112.Enoka RM, Robinson GA, Kossev AR. A stable, selective electrode for recording single motor‐unit potentials in humans. Exp Neurol 99: 761‐764, 1988.
 113.Ermilov LG, Mantilla CB, Rowley KL, Sieck GC. Safety factor for neuromuscular transmission at type‐identified diaphragm fibers. Muscle Nerve 35: 800‐803, 2007.
 114.Ermilov LG, Pulido JN, Atchison FW, Zhan WZ, Ereth MH, Sieck GC, Mantilla CB. Impairment of diaphragm muscle force and neuromuscular transmission after normothermic cardiopulmonary bypass: Effect of low dose inhaled CO. Am J Physiol Regul Integr Comp Physiol 298: R784‐R789, 2010.
 115.Eshed‐Eisenbach Y, Peles E. The clustering of voltage‐gated sodium channels in various excitable membranes. Dev Neurobiol 81 (5): 427‐437, 2019. DOI: 10.1002/dneu.22728.
 116.Falls DL, Rosen KM, Corfas G, Lane WS, Fischbach GD. ARIA, a protein that stimulates acetylcholine receptor synthesis, is a member of the neu ligand family. Cell 72: 801‐815, 1993.
 117.Fambrough DM, Drachman DB, Satyamurti S. Neuromuscular junction in myasthenia gravis: Decreased acetylcholine receptors. Science 182: 293‐295, 1973.
 118.Fatt P, Katz B. An analysis of the end‐plate potential recorded with an intra‐cellular electrode. J Physiol 115: 320‐370, 1951.
 119.Fatt P, Katz B. Spontaneous subthreshold activity at motor nerve endings. J Physiol 117: 109‐128, 1952.
 120.Favero M, Busetto G, Cangiano A. Spike timing plays a key role in synapse elimination at the neuromuscular junction. Proc Natl Acad Sci U S A 109: E1667‐E1675, 2012.
 121.Favero M, Massella O, Cangiano A, Buffelli M. On the mechanism of action of muscle fibre activity in synapse competition and elimination at the mammalian neuromuscular junction. Eur J Neurosci 29: 2327‐2334, 2009.
 122.Feldman JD, Bazzy AR, Cummins TR, Haddad GG. Developmental changes in neuromuscular transmission in the rat diaphragm. J Appl Physiol 71: 280‐286, 1991.
 123.Feng Z, Ko CP. The role of glial cells in the formation and maintenance of the neuromuscular junction. Ann N Y Acad Sci 1132: 19‐28, 2008.
 124.Fertuck HC, Salpeter MM. Localization of acetylcholine receptor by 125I‐labeled alpha‐bungarotoxin binding at mouse motor endplates. Proc Natl Acad Sci U S A 71: 1376‐1378, 1974.
 125.Fish LA, Fallon JR. Multiple MuSK signaling pathways and the aging neuromuscular junction. Neurosci Lett 731: 135014, 2020.
 126.Fleshman JW, Munson JB, Sypert GW, Friedman WA. Rheobase, input resistance, and motor‐unit type in medial gastrocnemius motoneurons in the cat. J Neurophysiol 46: 1326‐1338, 1981.
 127.Flucher BE, Daniels MP. Distribution of Na+ channels and ankyrin in neuromuscular junctions is complementary to that of acetylcholine receptors and the 43 kd protein. Neuron 3: 163‐175, 1989.
 128.Fogarty MJ. The bigger they are the harder they fall: Size‐dependent vulnerability of motor neurons in amyotrophic lateral sclerosis. J Physiol 596: 2471‐2472, 2018.
 129.Fogarty MJ. Driven to decay: Excitability and synaptic abnormalities in amyotrophic lateral sclerosis. Brain Res Bull 140: 318‐333, 2018.
 130.Fogarty MJ, Brandenburg JE, Sieck GC. Diaphragm neuromuscular transmission failure in a mouse model of an early‐onset neuromotor disorder. J Appl Physiol (1985) 130 (3): 708‐720, 2021. DOI: 10.1152/japplphysiol.00864.2020.
 131.Fogarty MJ, Gonzalez Porras MA, Mantilla CB, Sieck GC. Diaphragm neuromuscular transmission failure in aged rats. J Neurophysiol 122: 93‐104, 2019.
 132.Fogarty MJ, Hammond LA, Kanjhan R, Bellingham MC, Noakes PG. A method for the three‐dimensional reconstruction of Neurobiotin‐filled neurons and the location of their synaptic inputs. Front Neural Circuits 7: 153, 2013.
 133.Fogarty MJ, Kanjhan R, Bellingham MC, Noakes PG. Glycinergic neurotransmission: A potent regulator of embryonic motor neuron dendritic morphology and synaptic plasticity. J Neurosci 36: 80‐87, 2016.
 134.Fogarty MJ, Kanjhan R, Yanagawa Y, Noakes PG, Bellingham MC. Alterations in hypoglossal motor neurons due to GAD67 and VGAT deficiency in mice. Exp Neurol 289: 117‐127, 2017.
 135.Fogarty MJ, Mu EWH, Lavidis NA, Noakes PG, Bellingham MC. Size‐dependent dendritic maladaptations of hypoglossal motor neurons in SOD1(G93A) mice. Anat Rec (Hoboken) 304 (7): 1562‐1581, 2021. DOI: 10.1002/ar.24542.
 136.Fogarty MJ, Mu EWH, Lavidis NA, Noakes PG, Bellingham MC. Size‐dependent vulnerability of lumbar motor neuron dendritic degeneration in SOD1(G93A) mice. Anat Rec (Hoboken) 303: 1455‐1471, 2020.
 137.Fogarty MJ, Omar TS, Zhan WZ, Mantilla CB, Sieck GC. Phrenic motor neuron loss in aged rats. J Neurophysiol 119: 1852‐1862, 2018.
 138.Fogarty MJ, Sieck GC. Evolution and functional differentiation of the diaphragm muscle of mammals. Compr Physiol 9: 715‐766, 2019.
 139.Fogarty MJ, Sieck GC, Brandenburg JE. Impaired neuromuscular transmission of the tibialis anterior in a rodent model of hypertonia. J Neurophysiol 123: 1864‐1869, 2020.
 140.Fogarty MJ, Smallcombe KL, Yanagawa Y, Obata K, Bellingham MC, Noakes PG. Genetic deficiency of GABA differentially regulates respiratory and non‐respiratory motor neuron development. PLoS One 8: e56257, 2013.
 141.Fogarty MJ, Yanagawa Y, Obata K, Bellingham MC, Noakes PG. Genetic absence of the vesicular inhibitory amino acid transporter differentially regulates respiratory and locomotor motor neuron development. Brain Struct Funct 220: 525‐540, 2015.
 142.Fournier M, Alula M, Sieck GC. Neuromuscular transmission failure during postnatal development. Neurosci Lett 125: 34‐36, 1991.
 143.Fournier M, Sieck GC. Physiological properties of diaphragm motor units. Neurosci Abstr 10: 789, 1984.
 144.Fournier M, Sieck GC. Mechanical properties of muscle units in the cat diaphragm. J Neurophysiol 59: 1055‐1066, 1988.
 145.Fournier M, Sieck GC. Somatotopy in the segmental innervation of the cat diaphragm. J Appl Physiol 64: 291‐298, 1988.
 146.Fowles JR, Green HJ, Ouyang J. Na+‐K+‐ATPase in rat skeletal muscle: Content, isoform, and activity characteristics. J Appl Physiol 96: 316, 2004‐326, 1985.
 147.Frank E, Fischbach GD. Early events in neuromuscular junction formation in vitro. J Cell Biol 83: 143‐158, 1979.
 148.Frey D, Schneider C, Xu L, Borg J, Spooren W, Caroni P. Early and selective loss of neuromuscular synapse subtypes with low sprouting competence in motoneuron diseases. J Neurosci 20: 2534‐2542, 2000.
 149.Fukudome T, Shibuya N, Yoshimura T, Eguchi K. Short‐term effects of prednisolone on neuromuscular transmission in the isolated mdx mouse diaphragm. Tohoku J Exp Med 192: 211‐217, 2000.
 150.Gale AN, Gomez S, Duchen LW. Changes produced by a hypomyelinating neuropathy in muscle and its innervation. Morphological and physiological studies in the Trembler mouse. Brain 105: 373‐393, 1982.
 151.Garcia N, Tomas M, Santafe MM, Besalduch N, Lanuza MA, Tomas J. The interaction between tropomyosin‐related kinase B receptors and presynaptic muscarinic receptors modulates transmitter release in adult rodent motor nerve terminals. J Neurosci 30: 16514‐16522, 2010.
 152.Garcia N, Tomas M, Santafe MM, Lanuza MA, Besalduch N, Tomas J. Localization of brain‐derived neurotrophic factor, neurotrophin‐4, tropomyosin‐related kinase b receptor, and p75 NTR receptor by high‐resolution immunohistochemistry on the adult mouse neuromuscular junction. J Peripher Nerv Syst 15: 40‐49, 2010.
 153.Garcia N, Tomas M, Santafe MM, Lanuza MA, Besalduch N, Tomas J. Blocking p75 (NTR) receptors alters polyinnervationz of neuromuscular synapses during development. J Neurosci Res 89: 1331‐1341, 2011.
 154.Garcia‐Lopez P, Garcia‐Marin V, Freire M. The histological slides and drawings of cajal. Front Neuroanat 4: 9, 2010.
 155.Gasser HS, Grundfest H. Axon diameters in relation to the spike dimensions and the conduction velocity in mammalian A fibers. Am J Phys 127: 393‐414, 1939.
 156.Geevasinga N, Menon P, Ozdinler PH, Kiernan MC, Vucic S. Pathophysiological and diagnostic implications of cortical dysfunction in ALS. Nat Rev Neurol 12: 651‐661, 2016.
 157.Geiger PC, Bailey JP, Mantilla CB, Zhan WZ, Sieck GC. Mechanisms underlying myosin heavy chain expression during development of the rat diaphragm muscle. J Appl Physiol 101: 1546‐1555, 2006.
 158.Geiger PC, Cody MJ, Macken RL, Sieck GC. Maximum specific force depends on myosin heavy chain content in rat diaphragm muscle fibers. J Appl Physiol 89: 695‐703, 2000.
 159.Geiger PC, Cody MJ, Sieck GC. Force‐calcium relationship depends on myosin heavy chain and troponin isoforms in rat diaphragm muscle fibers. J Appl Physiol 87: 1894‐1900, 1999.
 160.Gellerich FN, Gizatullina Z, Arandarcikaite O, Jerzembek D, Vielhaber S, Seppet E, Striggow F. Extramitochondrial Ca2+ in the nanomolar range regulates glutamate‐dependent oxidative phosphorylation on demand. PLoS One 4: e8181, 2009.
 161.Georgiou J, Robitaille R, Charlton MP. Muscarinic control of cytoskeleton in perisynaptic glia. J Neurosci 19: 3836‐3846, 1999.
 162.Gerlach J. Von den Ruckenmarke. Leipzig: Engelmann, 1871.
 163.Ghazanfari N, Linsao EL, Trajanovska S, Morsch M, Gregorevic P, Liang SX, Reddel SW, Phillips WD. Forced expression of muscle specific kinase slows postsynaptic acetylcholine receptor loss in a mouse model of MuSK myasthenia gravis. Physiol Rep 3: e12658, 2015.
 164.Gilhus NE, Tzartos S, Evoli A, Palace J, Burns TM, Verschuuren J. Myasthenia gravis. Nat Rev Dis Primers 5: 30, 2019.
 165.Gillon A, Sheard P. Elderly mouse skeletal muscle fibres have a diminished capacity to upregulate NCAM production in response to denervation. Biogerontology 16: 811‐823, 2015.
 166.Glavinovic MI. Change of statistical parameters of transmitter release during various kinetic tests in unparalysed voltage‐clamped rat diaphragm. J Physiol 290: 481‐497, 1979.
 167.Golgi C. Sulla sostanza grigia del cervello. Gazetta Medica Italiana 33: 244‐246, 1873.
 168.Gonzalez Porras MA, Fogarty MJ, Gransee HM, Sieck GC, Mantilla CB. Frequency‐dependent lipid raft uptake at rat diaphragm muscle axon terminals. Muscle Nerve 59: 611‐618, 2019.
 169.Goonasekera SA, Lam CK, Millay DP, Sargent MA, Hajjar RJ, Kranias EG, Molkentin JD. Mitigation of muscular dystrophy in mice by SERCA overexpression in skeletal muscle. J Clin Invest 121: 1044‐1052, 2011.
 170.Gotti C, Clementi F, Fornari A, Gaimarri A, Guiducci S, Manfredi I, Moretti M, Pedrazzi P, Pucci L, Zoli M. Structural and functional diversity of native brain neuronal nicotinic receptors. Biochem Pharmacol 78: 703‐711, 2009.
 171.Gowers WR. A Manual of Diseases of the Nervous System. P. Blakiston, Son & Company, 1898.
 172.Green HJ, Duhamel TA, Holloway GP, Moule JW, Ouyang J, Ranney D, Tupling AR. Muscle Na+‐K+‐ATPase response during 16 h of heavy intermittent cycle exercise. Am J Physiol Endocrinol Metab 293: E523‐E530, 2007.
 173.Greer JJ, Allan DW, Martin‐Caraballo M, Lemke RP. An overview of phrenic nerve and diaphragm muscle development in the perinatal rat. J Appl Physiol 86: 779‐786, 1999.
 174.Greer JJ, Smith JC, Feldman JL. Respiratory and locomotor patterns generated in the fetal rat brain stem‐spinal cord in vitro. J Neurophysiol 67: 996‐999, 1992.
 175.Greising SM, Ermilov LG, Sieck GC, Mantilla CB. Ageing and neurotrophic signalling effects on diaphragm neuromuscular function. J Physiol 593: 431‐440, 2015.
 176.Greising SM, Gransee HM, Mantilla CB, Sieck GC. Systems biology of skeletal muscle: Fiber type as an organizing principle. Wiley Interdiscip Rev Syst Biol Med 4: 457‐473, 2012.
 177.Greising SM, Stowe JM, Sieck GC, Mantilla CB. Role of TrkB kinase activity in aging diaphragm neuromuscular junctions. Exp Gerontol 72: 184‐191, 2015.
 178.Greising SM, Vasdev AK, Zhan WZ, Sieck GC, Mantilla CB. Chronic TrkB agonist treatment in old age does not mitigate diaphragm neuromuscular dysfunction. Physiol Rep 5: e13103, 2017.
 179.Grossman Y, Parnas I, Spira ME. Differential conduction block in branches of a bifurcating axon. J Physiol 295: 283‐305, 1979.
 180.Gundersen CB. The structure of the synaptic vesicle‐plasma membrane interface constrains SNARE models of rapid, synchronous exocytosis at nerve terminals. Front Mol Neurosci 10: 48, 2017.
 181.Haase G, Dessaud E, Garces A, de Bovis B, Birling M, Filippi P, Schmalbruch H, Arber S, deLapeyriere O. GDNF acts through PEA3 to regulate cell body positioning and muscle innervation of specific motor neuron pools. Neuron 35: 893‐905, 2002.
 182.Hall ZW, Sanes JR. Synaptic structure and development: The neuromuscular junction. Cell 72 (Suppl): 99‐121, 1993.
 183.Hamalainen N, Pette D. Myosin and SERCA isoform expression in denervated slow‐twitch muscle of euthyroid and hyperthyroid rabbits. J Muscle Res Cell Motil 22: 453‐457, 2001.
 184.Hanson PI, Roth R, Morisaki H, Jahn R, Heuser JE. Structure and conformational changes in NSF and its membrane receptor complexes visualized by quick‐freeze/deep‐etch electron microscopy. Cell 90: 523‐535, 1997.
 185.Harris AJ. Embryonic growth and innervation of rat skeletal muscles. I neural regulation of muscle fibre numbers. Philos Trans R Soc Lond Ser B Biol Sci 293: 257‐277, 1981.
 186.Harris AJ. Embryonic growth and innervation of rat skeletal muscles. III. Neural regulation of junctional and extra‐junctional acetylcholine receptor clusters. Philos Trans R Soc Lond Ser B Biol Sci 293: 287‐314, 1981.
 187.Harris JJ, Jolivet R, Attwell D. Synaptic energy use and supply. Neuron 75: 762‐777, 2012.
 188.Hayworth CR, Moody SE, Chodosh LA, Krieg P, Rimer M, Thompson WJ. Induction of neuregulin signaling in mouse schwann cells in vivo mimics responses to denervation. J Neurosci 26: 6873‐6884, 2006.
 189.Heeroma JH, Roelandse M, Wierda K, van Aerde KI, Toonen RF, Hensbroek RA, Brussaard A, Matus A, Verhage M. Trophic support delays but does not prevent cell‐intrinsic degeneration of neurons deficient for munc18‐1. Eur J Neurosci 20: 623‐634, 2004.
 190.Hegedus J, Putman CT, Gordon T. Time course of preferential motor unit loss in the SOD1 G93A mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 28: 154‐164, 2007.
 191.Hegedus J, Putman CT, Tyreman N, Gordon T. Preferential motor unit loss in the SOD1 G93A transgenic mouse model of amyotrophic lateral sclerosis. J Physiol 586: 3337‐3351, 2008.
 192.Henderson R, Baumann F, Hutchinson N, McCombe P. CMAP decrement in ALS. Muscle Nerve 39: 555‐556, 2009.
 193.Henneman E, Somjen G, Carpenter DO. Functional significance of cell size in spinal motoneurons. J Neurophysiol 28: 560‐580, 1965.
 194.Herrera AA, Qiang H, Ko CP. The role of perisynaptic Schwann cells in development of neuromuscular junctions in the frog (Xenopus laevis). J Neurobiol 45: 237‐254, 2000.
 195.Heuser JE, Reese TS. Evidence for recycling of synaptic vesicle membrane during transmitter release at the frog neuromuscular junction. J Cell Biol 57: 315‐344, 1973.
 196.Heuser JE, Reese TS, Dennis MJ, Jan Y, Jan L, Evans L. Synaptic vesicle exocytosis captured by quick freezing and correlated with quantal transmitter release. J Cell Biol 81: 275‐300, 1979.
 197.Higuchi O, Hamuro J, Motomura M, Yamanashi Y. Autoantibodies to low‐density lipoprotein receptor‐related protein 4 in myasthenia gravis. Ann Neurol 69: 418‐422, 2011.
 198.Hoch W, McConville J, Helms S, Newsom‐Davis J, Melms A, Vincent A. Auto‐antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med 7: 365‐368, 2001.
 199.Hounsgaard J. Motor neurons. Compr Physiol 7: 463‐484, 2017.
 200.Hughes SM, Koishi K, Rudnicki M, Maggs AM. MyoD protein is differentially accumulated in fast and slow skeletal muscle fibres and required for normal fibre type balance in rodents. Mech Dev 61: 151‐163, 1997.
 201.Hughes SM, Taylor JM, Tapscott SJ, Gurley CM, Carter WJ, Peterson CA. Selective accumulation of MyoD and myogenin mRNAs in fast and slow adult skeletal muscle is controlled by innervation and hormones. Development 118: 1137‐1147, 1993.
 202.Hundal HS, Marette A, Ramlal T, Liu Z, Klip A. Expression of beta subunit isoforms of the Na+, K(+)‐ATPase is muscle type‐specific. FEBS Lett 328: 253‐258, 1993.
 203.Inoue A, Setoguchi K, Matsubara Y, Okada K, Sato N, Iwakura Y, Higuchi O, Yamanashi Y. Dok‐7 activates the muscle receptor kinase MuSK and shapes synapse formation. Sci Signal 2: ra7, 2009.
 204.Jahromi BS, Robitaille R, Charlton MP. Transmitter release increases intracellular calcium in perisynaptic Schwann cells in situ. Neuron 8: 1069‐1077, 1992.
 205.Jang YC, Van Remmen H. Age‐associated alterations of the neuromuscular junction. Exp Gerontol 46: 193‐198, 2011.
 206.Jansen JKS, Fladby T. The perinatal organization of the innervation of skeletal muscle in mammals. Prog Neurobiol 34: 39‐90, 1990.
 207.Je HS, Yang F, Ji Y, Potluri S, Fu XQ, Luo ZG, Nagappan G, Chan JP, Hempstead B, Son YJ, Lu B. ProBDNF and mature BDNF as punishment and reward signals for synapse elimination at mouse neuromuscular junctions. J Neurosci 33: 9957‐9962, 2013.
 208.Jessen KR, Mirsky R. Embryonic Schwann cell development: The biology of Schwann cell precursors and early Schwann cells. J Anat 191 (Pt 4): 501‐505, 1997.
 209.Jessen KR, Mirsky R. Origin and early development of Schwann cells. Microsc Res Tech 41: 393‐402, 1998.
 210.Ji H, Coleman J, Yang R, Melia TJ, Rothman JE, Tareste D. Protein determinants of SNARE‐mediated lipid mixing. Biophys J 99: 553‐560, 2010.
 211.Jo SA, Zhu X, Marchionni MA, Burden SJ. Neuregulins are concentrated at nerve‐muscle synapses and activate ACh‐receptor gene expression. Nature 373: 158‐161, 1995.
 212.Johansson C, Lunde PK, Gothe S, Lannergren J, Westerblad H. Isometric force and endurance in skeletal muscle of mice devoid of all known thyroid hormone receptors. J Physiol 547: 789‐796, 2003.
 213.Johnson BD, Sieck GC. Differential susceptibility of diaphragm muscle fibers to neuromuscular transmission failure. J Appl Physiol 75: 341‐348, 1993.
 214.Johnson BD, Wilson LE, Zhan WZ, Watchko JF, Daood MJ, Sieck GC. Contractile properties of the developing diaphragm correlate with myosin heavy chain phenotype. J Appl Physiol 77: 481‐487, 1994.
 215.Johnson H, Hokfelt T, Ulfhake B. Expression of p75(NTR), trkB and trkC in nonmanipulated and axotomized motoneurons of aged rats. Brain Res Mol Brain Res 69: 21‐34, 1999.
 216.Jones RA, Harrison C, Eaton SL, Llavero Hurtado M, Graham LC, Alkhammash L, Oladiran OA, Gale A, Lamont DJ, Simpson H, Simmen MW, Soeller C, Wishart TM, Gillingwater TH. Cellular and molecular anatomy of the human neuromuscular junction. Cell Rep 21: 2348‐2356, 2017.
 217.Joyce NC, Carter GT. Electrodiagnosis in persons with amyotrophic lateral sclerosis. PM R 5: S89‐S95, 2013.
 218.Kaeser PS, Sudhof TC. RIM function in short‐ and long‐term synaptic plasticity. Biochem Soc Trans 33: 1345‐1349, 2005.
 219.Katz B, Miledi R. Propagation of electric activity in motor nerve terminals. Proc R Soc Lond 161: 453‐482, 1965.
 220.Katz B, Miledi R. The release of acetylcholine from nerve endings by graded electric pulses. Proc R Soc Lond B Biol Sci 167: 23‐38, 1967.
 221.Katz B, Miledi R. The timing of calcium action during neuromuscular transmission. J Physiol 189: 535‐544, 1967.
 222.Katz B, Miledi R. Transmitter leakage from motor nerve endings. Proc R Soc Lond B Biol Sci 196: 59‐72, 1977.
 223.Katz B, Thesleff S. On the factors which determine the amplitude of the ‘miniature end‐plate potential’. J Physiol 137: 267‐278, 1957.
 224.Katz B, Thesleff S. A study of the desensitization produced by acetylcholine at the motor end‐plate. J Physiol 138: 63‐80, 1957.
 225.Khurram OU, Fogarty MJ, Rana S, Vang P, Sieck GC, Mantilla CB. Diaphragm muscle function following mid‐cervical contusion injury in rats. J Appl Physiol (1985) 126 (1): 221‐230, 2018. DOI:10.1152/japplphysiol.00481
 226.Khurram OU, Fogarty MJ, Sarrafian TL, Bhatt A, Mantilla CB, Sieck GC. Impact of aging on diaphragm muscle function in male and female Fischer 344 rats. Physiol Rep 6: e13786, 2018.
 227.Kiernan JA, Hudson AJ. Changes in sizes of cortical and lower motor neurons in amyotrophic lateral sclerosis. Brain 114 (Pt 2): 843‐853, 1991.
 228.Knudsen KA. Cell adhesion molecules in myogenesis. Curr Opin Cell Biol 2: 902‐906, 1990.
 229.Kong XC, Barzaghi P, Ruegg MA. Inhibition of synapse assembly in mammalian muscle in vivo by RNA interference. EMBO Rep 5: 183‐188, 2004.
 230.Kononenko NL, Diril MK, Puchkov D, Kintscher M, Koo SJ, Pfuhl G, Winter Y, Wienisch M, Klingauf J, Breustedt J, Schmitz D, Maritzen T, Haucke V. Compromised fidelity of endocytic synaptic vesicle protein sorting in the absence of stonin 2. Proc Natl Acad Sci U S A 110: E526‐E535, 2013.
 231.Krause W. Die Entladungshypothese und die motorischen Endplatten. Arch Mikrosk Anat 13: 170‐179, 1877.
 232.Krauss RS, Cole F, Gaio U, Takaesu G, Zhang W, Kang JS. Close encounters: Regulation of vertebrate skeletal myogenesis by cell‐cell contact. J Cell Sci 118: 2355‐2362, 2005.
 233.Kravtsova VV, Bouzinova EV, Chibalin AV, Matchkov VV, Krivoi II. Isoform‐specific Na, K‐ATPase and membrane cholesterol remodeling in motor endplates in distinct mouse models of myodystrophy. Am J Physiol Cell Physiol 318: C1030‐C1041, 2020.
 234.Krnjevic K, Miledi R. Failure of neuromuscular propagation in rats. J Physiol 140: 440‐461, 1958.
 235.Krnjevic K, Miledi R. Motor units in the rat diaphragm. J Physiol 140: 427‐439, 1958.
 236.Krnjevic K, Miledi R. Presynaptic failure of neuromuscular propagation in rats. J Physiol Lond 149: 1‐22, 1959.
 237.Kucenas S, Takada N, Park HC, Woodruff E, Broadie K, Appel B. CNS‐derived glia ensheath peripheral nerves and mediate motor root development. Nat Neurosci 11: 143‐151, 2008.
 238.Kuei JH, Shadmehr R, Sieck GC. Relative contribution of neurotransmission failure to diaphragm fatigue. J Appl Physiol 68: 174‐180, 1990.
 239.Kuffler SW, Yoshikami D. The number of transmitter molecules in a quantum: An estimate from iontophoretic application of acetylcholine at the neuromuscular synapse. J Physiol 251: 465‐482, 1975.
 240.Kummel D, Krishnakumar SS, Radoff DT, Li F, Giraudo CG, Pincet F, Rothman JE, Reinisch KM. Complexin cross‐links prefusion SNAREs into a zigzag array. Nat Struct Mol Biol 18: 927‐933, 2011.
 241.Kummer TT, Misgeld T, Sanes JR. Assembly of the postsynaptic membrane at the neuromuscular junction: Paradigm lost. Curr Opin Neurobiol 16: 74‐82, 2006.
 242.Kurihara T. Seronegative myasthenia gravis and muscle atrophy of the tongue. Intern Med 44: 536‐537, 2005.
 243.Labovitz SS, Robbins N, Fahim MA. Endplate topgraphy of denervated and disused rat neuromuscular junctions: Comparison by scanning and light microscopy. Neuroscience 11 (4): 963‐971, 1984.
 244.Lambert EH, Lindstrom JM, Lennon VA. End‐plate potentials in experimental autoimmune myasthenia gravis in rats. Ann N Y Acad Sci 274: 300‐318, 1976.
 245.Land BR, Harris WV, Salpeter EE, Salpeter MM. Diffusion and binding constants for acetylcholine derived from the falling phase of miniature endplate currents. Proc Natl Acad Sci U S A 81: 1594‐1598, 1984.
 246.Land BR, Salpeter EE, Salpeter MM. Kinetic parameters for acetylcholine interaction in intact neuromuscular junction. Proc Natl Acad Sci U S A 78: 7200‐7204, 1981.
 247.Landmesser L. The relationship of intramuscular nerve branching and synaptogenesis to motoneuron survival. J Neurobiol 23: 1131‐1139, 1992.
 248.Langley JN. On the reaction of cells and of nerve‐endings to certain poisons, chiefly as regards the reaction of striated muscle to nicotine and to curari. J Physiol 33: 374‐413, 1905.
 249.Laskowski MB, Sanes JR. Topographic mapping of motor pools onto skeletal muscles. J Neurosci 7: 252‐260, 1987.
 250.Laughlin SB, de Ruyter van Steveninck RR, Anderson JC. The metabolic cost of neural information. Nat Neurosci 1: 36‐41, 1998.
 251.Lebrasseur NK, Cote GM, Miller TA, Fielding RA, Sawyer DB. Regulation of neuregulin/ErbB signaling by contractile activity in skeletal muscle. Am J Physiol Cell Physiol 284: C1149‐C1155, 2003.
 252.Lee CW, Zhang H, Geng L, Peng HB. Crosslinking‐induced endocytosis of acetylcholine receptors by quantum dots. PLoS One 9: e90187, 2014.
 253.Lee KM, Chand KK, Hammond LA, Lavidis NA, Noakes PG. Functional decline at the aging neuromuscular junction is associated with altered laminin‐alpha4 expression. Aging (Albany NY) 9: 880‐899, 2017.
 254.Lee YI, Li Y, Mikesh M, Smith I, Nave KA, Schwab MH, Thompson WJ. Neuregulin1 displayed on motor axons regulates terminal Schwann cell‐mediated synapse elimination at developing neuromuscular junctions. Proc Natl Acad Sci U S A 113: E479‐E487, 2016.
 255.Lennon VA, Lambert EH. Myasthenia gravis induced by monoclonal antibodies to acetylcholine receptors. Nature 285: 238‐240, 1980.
 256.Lewis WH. The development of the muscular system. In: Manual of Human Embryology. Philadelphia, PA: Lippincott, 1910, p. 454‐522.
 257.Li P, Steinbach JH. The neuronal nicotinic alpha4beta2 receptor has a high maximal probability of being open. Br J Pharmacol 160: 1906‐1915, 2010.
 258.Li XM, Dong XP, Luo SW, Zhang B, Lee DH, Ting AK, Neiswender H, Kim CH, Carpenter‐Hyland E, Gao TM, Xiong WC, Mei L. Retrograde regulation of motoneuron differentiation by muscle beta‐catenin. Nat Neurosci 11: 262‐268, 2008.
 259.Liddell EGT, Sherrington CS. Recruitment and some other factors of reflex inhibition. Proc Roy Soc Lond (Biol) 97: 488‐518, 1925.
 260.Lin S, Landmann L, Ruegg MA, Brenner HR. The role of nerve‐ versus muscle‐derived factors in mammalian neuromuscular junction formation. J Neurosci 28: 3333‐3340, 2008.
 261.Ling G, Gerard RW. The normal membrane potential of frog sartorius fibers. J Cell Comp Physiol 34: 383‐396, 1949.
 262.Liu C, Bickford LS, Held RG, Nyitrai H, Sudhof TC, Kaeser PS. The active zone protein family ELKS supports Ca2+ influx at nerve terminals of inhibitory hippocampal neurons. J Neurosci 34: 12289‐12303, 2014.
 263.Lubischer JL, Bebinger DM. Regulation of terminal Schwann cell number at the adult neuromuscular junction. J Neurosci 19: RC46, 1999.
 264.Lupa MT, Gordon H, Hall ZW. A specific effect of muscle cells on the distribution of presynaptic proteins in neurites and its absence in a C2 muscle cell variant. Dev Biol 142: 31‐43, 1990.
 265.Lytton J, Westlin M, Burk SE, Shull GE, MacLennan DH. Functional comparisons between isoforms of the sarcoplasmic or endoplasmic reticulum family of calcium pumps. J Biol Chem 267: 14483‐14489, 1992.
 266.Ma KH, Duong P, Moran JJ, Junaidi N, Svaren J. Polycomb repression regulates Schwann cell proliferation and axon regeneration after nerve injury. Glia 66: 2487‐2502, 2018.
 267.Madhavan R, Zhao XT, Ruegg MA, Peng HB. Tyrosine phosphatase regulation of MuSK‐dependent acetylcholine receptor clustering. Mol Cell Neurosci 28: 403‐416, 2005.
 268.Maggio S, Ceccaroli P, Polidori E, Cioccoloni A, Stocchi V, Guescini M. Signal exchange through extracellular vesicles in neuromuscular junction establishment and maintenance: From physiology to pathology. Int J Mol Sci 20: 2804, 2019.
 269.Mallart A, Dreyer F, Peper K. Current‐voltage relation and reversal potential at junctional and extrajunctional ACh‐receptors of the frog neuromuscular junction. Pflugers Arch 362: 43‐47, 1976.
 270.Mantilla CB, Fahim MA, Sieck GC. Functional development of respiratory muscles. In: Polin RA, Fox WW, Abman SH, editors. Fetal and Neonatal Physiology (4th ed). W.B. Saunders, 2011, p. 937‐952. DOI: 10.1016/B978-1-4160-3479-7.10085-0.
 271.Mantilla CB, Rowley KL, Fahim MA, Zhan WZ, Sieck GC. Synaptic vesicle cycling at type‐identified diaphragm neuromuscular junctions. Muscle Nerve 30: 774‐783, 2004.
 272.Mantilla CB, Rowley KL, Zhan WZ, Fahim MA, Sieck GC. Synaptic vesicle pools at diaphragm neuromuscular junctions vary with motoneuron soma, not axon terminal, inactivity. Neuroscience 146: 178‐189, 2007.
 273.Mantilla CB, Seven YB, Zhan WZ, Sieck GC. Diaphragm motor unit recruitment in rats. Respir Physiol Neurobiol 173: 101‐106, 2010.
 274.Mantilla CB, Sieck GC. Invited Review: Mechanisms underlying motor unit plasticity in the respiratory system. J Appl Physiol 94: 1230‐1241, 2003.
 275.Mantilla CB, Sieck GC. Key aspects of phrenic motoneuron and diaphragm muscle development during the perinatal period. J Appl Physiol 104: 1818‐1827, 2008.
 276.Mantilla CB, Sieck GC. Key aspects of phrenic motoneuron and diaphragm muscle development during the perinatal period. J Appl Physiol, 2008.
 277.Mantilla CB, Sill RV, Aravamudan B, Zhan WZ, Sieck GC. Developmental effects on myonuclear domain size of rat diaphragm fibers. J Appl Physiol 104: 787‐794, 2008.
 278.Mantilla CB, Zhan WZ, Sieck GC. Neurotrophins improve neuromuscular transmission in the adult rat diaphragm. Muscle Nerve 29: 381‐386, 2004.
 279.Mantilla CB, Zhan WZ, Sieck GC. Retrograde labeling of phrenic motoneurons by intrapleural injection. J Neurosci Methods 182: 244‐249, 2009.
 280.Manuel M, Zytnicki D. Molecular and electrophysiological properties of mouse motoneuron and motor unit subtypes. Curr Opin Physio 8: 23‐29, 2019.
 281.Marques MJ, Conchello JA, Lichtman JW. From plaque to pretzel: Fold formation and acetylcholine receptor loss at the developing neuromuscular junction. J Neurosci 20: 3663‐3675, 2000.
 282.Martignago S, Fanin M, Albertini E, Pegoraro E, Angelini C. Muscle histopathology in myasthenia gravis with antibodies against MuSK and AChR. Neuropathol Appl Neurobiol 35: 103‐110, 2009.
 283.Martin A. Junctional transmission II. Presynaptic mechanisms. Compr Physiol: 329‐355, 2011.
 284.Martin AR. Amplification of neuromuscular transmission by postjunctional folds. Proc Biol Sci 258: 321‐326, 1994.
 285.Martineau E, Di Polo A, Vande Velde C, Robitaille R. Dynamic neuromuscular remodeling precedes motor‐unit loss in a mouse model of ALS. elife 7: e41973, 2018.
 286.Martineau E, Di Polo A, Vande Velde C, Robitaille R. Sex‐specific differences in motor‐unit remodeling in a mouse model of ALS. eNeuro 7, 2020.
 287.Martinez‐Valencia A, Ramirez‐Santiago G, De‐Miguel FF. Dynamics of neuromuscular transmission reproduced by calcium‐dependent and reversible serial transitions in the vesicle fusion complex. Front Synaptic Neurosci 13: 785361, 2021.
 288.Matthews‐Bellinger JA, Salpeter MM. Fine structural distribution of acetylcholine receptors at developing mouse neuromuscular junctions. J Neurosci 3: 644‐657, 1983.
 289.Mazala DA, Pratt SJP, Chen D, Molkentin JD, Lovering RM, Chin ER. SERCA1 overexpression minimizes skeletal muscle damage in dystrophic mouse models. Am J Physiol Cell Physiol 308: C699‐C709, 2015.
 290.McMahan UJ. The agrin hypothesis. Cold Spring Harb Symp Quant Biol 55: 407‐418, 1990.
 291.McMorrow C, Fredsted A, Carberry J, O'Connell RA, Bradford A, Jones JF, O'Halloran KD. Chronic hypoxia increases rat diaphragm muscle endurance and sodium‐potassium ATPase pump content. Eur Respir J 37: 1474‐1481, 2011.
 292.Megighian A, Zordan M, Pantano S, Scorzeto M, Rigoni M, Zanini D, Rossetto O, Montecucco C. Evidence for a radial SNARE super‐complex mediating neurotransmitter release at the Drosophila neuromuscular junction. J Cell Sci 126: 3134‐3140, 2013.
 293.Merlie JP, Heinemann S, Einarson B, Lindstrom JM. Degradation of acetylcholine receptor in diaphragms of rats with experimental autoimmune myasthenia gravis. J Biol Chem 254: 6328‐6332, 1979.
 294.Mier‐Jedrzejowicz AK, Brophy C, Green M. Respiratory muscle function in myasthenia gravis. Am Rev Respir Dis 138: 867‐873, 1988.
 295.Milton RL, Lupa MT, Caldwell JH. Fast and slow twitch skeletal muscle fibres differ in their distribution of Na channels near the endplate. Neurosci Lett 135: 41‐44, 1992.
 296.Mirsky R, Jessen KR, Brennan A, Parkinson D, Dong Z, Meier C, Parmantier E, Lawson D. Schwann cells as regulators of nerve development. J Physiol Paris 96: 17‐24, 2002.
 297.Miyazawa A, Fujiyoshi Y, Stowell M, Unwin N. Nicotinic acetylcholine receptor at 4.6 A resolution: Transverse tunnels in the channel wall. J Mol Biol 288: 765‐786, 1999.
 298.Miyoshi S, Tezuka T, Arimura S, Tomono T, Okada T, Yamanashi Y. DOK7 gene therapy enhances motor activity and life span in ALS model mice. EMBO Mol Med 9: 880‐889, 2017.
 299.Molenaar PC, Polak RL, Miledi R, Alema S, Vincent A, Newsom‐Davis J. Acetylcholine in intercostal muscle from myasthenia gravis patients and in rat diaphragm after blockade of acetylcholine receptors. Prog Brain Res 49: 449‐458, 1979.
 300.Montecucco C, Schiavo G, Pantano S. SNARE complexes and neuroexocytosis: How many, how close? Trends Biochem Sci 30: 367‐372, 2005.
 301.Mora M, Lambert EH, Engel AG. Synaptic vesicle abnormality in familial infantile myasthenia. Neurology 37: 206‐214, 1987.
 302.Mori S, Kubo S, Akiyoshi T, Yamada S, Miyazaki T, Hotta H, Desaki J, Kishi M, Konishi T, Nishino Y, Miyazawa A, Maruyama N, Shigemoto K. Antibodies against muscle‐specific kinase impair both presynaptic and postsynaptic functions in a murine model of myasthenia gravis. Am J Pathol 180: 798‐810, 2012.
 303.Morsch M, Reddel SW, Ghazanfari N, Toyka KV, Phillips WD. Pyridostigmine but not 3, 4‐diaminopyridine exacerbates ACh receptor loss and myasthenia induced in mice by muscle‐specific kinase autoantibody. J Physiol 591: 2747‐2762, 2013.
 304.Muniak CG, Kriebel ME, Carlson CG. Changes in MEPP and EPP amplitude distributions in the mouse diaphragm during synapse formation and degeneration. Dev Brain Res 5: 123‐138, 1982.
 305.Muppidi S, Guptill JT, Jacob S, Li Y, Farrugia ME, Guidon AC, Tavee JO, Kaminski H, Howard JF Jr, Cutter G, Wiendl H, Maas MB, Illa I, Mantegazza R, Murai H, Utsugisawa K, Nowak RJ, Group C‐MS. COVID‐19‐associated risks and effects in myasthenia gravis (CARE‐MG). Lancet Neurol 19: 970‐971, 2020.
 306.Murphy RM, Larkins NT, Mollica JP, Beard NA, Lamb GD. Calsequestrin content and SERCA determine normal and maximal Ca2+ storage levels in sarcoplasmic reticulum of fast‐ and slow‐twitch fibres of rat. J Physiol 587: 443‐460, 2009.
 307.Nagwaney S, Harlow ML, Jung JH, Szule JA, Ress D, Xu J, Marshall RM, McMahan UJ. Macromolecular connections of active zone material to docked synaptic vesicles and presynaptic membrane at neuromuscular junctions of mouse. J Comp Neurol 513: 457‐468, 2009.
 308.Nakashima H, Ohkawara B, Ishigaki S, Fukudome T, Ito K, Tsushima M, Konishi H, Okuno T, Yoshimura T, Ito M, Masuda A, Sobue G, Kiyama H, Ishiguro N, Ohno K. R‐spondin 2 promotes acetylcholine receptor clustering at the neuromuscular junction via Lgr5. Sci Rep 6: 28512, 2016.
 309.Narayanan CH, Fox MW, Hamburger V. Prenatal development of spontaneous and evoked activity in the rat (Rattus norvegicus albinus). Behaviour 40: 100‐134, 1971.
 310.Nascimento F, Pousinha PA, Correia AM, Gomes R, Sebastiao AM, Ribeiro JA. Adenosine A2A receptors activation facilitates neuromuscular transmission in the pre‐symptomatic phase of the SOD1(G93A) ALS mice, but not in the symptomatic phase. PLoS One 9: e104081, 2014.
 311.Nastuk WLH, A.L. The electrical activity of single muscle fibers. J Cell Comp Physiol 35: 39‐73, 1950.
 312.Nemoto Y, Kuwabara S, Misawa S, Kawaguchi N, Hattori T, Takamori M, Vincent A. Patterns and severity of neuromuscular transmission failure in seronegative myasthenia gravis. J Neurol Neurosurg Psychiatry 76: 714‐718, 2005.
 313.Ngo ST, Baumann F, Ridall PG, Pettitt AN, Henderson RD, Bellingham MC, McCombe PA. The relationship between Bayesian motor unit number estimation and histological measurements of motor neurons in wild‐type and SOD1(G93A) mice. Clin Neurophysiol 123: 2080‐2091, 2012.
 314.Ngo ST, Cole RN, Sunn N, Phillips WD, Noakes PG. Neuregulin‐1 potentiates agrin‐induced acetylcholine receptor clustering through muscle‐specific kinase phosphorylation. J Cell Sci 125: 1531‐1543, 2012.
 315.Nguyen QT, Prasadanian AS, Snider WD, Lichtman JW. Hyperinnervation of neuromuscular junctions caused by GDNF overexpression in muscle. Science 279: 1725‐1729, 1998.
 316.Niks EH, Kuks JB, Wokke JH, Veldman H, Bakker E, Verschuuren JJ, Plomp JJ. Pre‐ and postsynaptic neuromuscular junction abnormalities in musk myasthenia. Muscle Nerve 42: 283‐288, 2010.
 317.Nishimaru H, Iizuka M, Ozaki S, Kudo N. Spontaneous motoneuronal activity mediated by glycine and GABA in the spinal cord of rat fetuses in vitro. J Physiol 497 (Pt 1): 131‐143, 1996.
 318.Norenberg MD, Rao KV. The mitochondrial permeability transition in neurologic disease. Neurochem Int 50: 983‐997, 2007.
 319.Nykjaer A, Willnow TE, Petersen CM. p75NTR‐‐live or let die. Curr Opin Neurobiol 15: 49‐57, 2005.
 320.O'Brien RA, Ostberg AJ, Vrbova G. Observations on the elimination of polyneuronal innervation in developing mammalian skeletal muscle. J Physiol 282: 571‐582, 1978.
 321.O'Brien RAD, Ostberg AJC, Vrbova G. Observations on the elimination of polyneuronal innervation in developing mammalian skeletal muscle. J Physiol 282: 571‐582, 1978.
 322.Oda K. Age changes of motor innervation and acetylcholine receptor distribution on human skeletal muscle fibres. J Neurol Sci 66: 327‐338, 1984.
 323.Ogata T. A histochemical study on the structural differences of motor endplate in the red, white and intermediate muscle fibers of mouse limb muscle. Acta Med Okayama 19: 149‐153, 1965.
 324.Ohnishi T, Yanazawa M, Sasahara T, Kitamura Y, Hiroaki H, Fukazawa Y, Kii I, Nishiyama T, Kakita A, Takeda H, Takeuchi A, Arai Y, Ito A, Komura H, Hirao H, Satomura K, Inoue M, Muramatsu S, Matsui K, Tada M, Sato M, Saijo E, Shigemitsu Y, Sakai S, Umetsu Y, Goda N, Takino N, Takahashi H, Hagiwara M, Sawasaki T, Iwasaki G, Nakamura Y, Nabeshima Y, Teplow DB, Hoshi M. Na, K‐ATPase alpha3 is a death target of Alzheimer patient amyloid‐beta assembly. Proc Natl Acad Sci U S A 112: E4465‐E4474, 2015.
 325.Okada K, Inoue A, Okada M, Murata Y, Kakuta S, Jigami T, Kubo S, Shiraishi H, Eguchi K, Motomura M, Akiyama T, Iwakura Y, Higuchi O, Yamanashi Y. The muscle protein Dok‐7 is essential for neuromuscular synaptogenesis. Science 312: 1802‐1805, 2006.
 326.Oppenheim RW. The neurotrophic theory and naturally occurring motoneuron death. Trends Neurosci 12: 252‐255, 1989.
 327.Oppenheim RW. Neurotrophic survival molecules for motoneurons: An embarrassment of riches. Neuron 17: 195‐197, 1996.
 328.Oppenheim RW, Caldero J, Cuitat D, Esquerda J, Ayala V, Prevette D, Wang S. Rescue of developing spinal motoneurons from programmed cell death by the GABA(A) agonist muscimol acts by blockade of neuromuscular activity and increased intramuscular nerve branching. Mol Cell Neurosci 22: 331‐343, 2003.
 329.Oppenheim RW, Caldero J, Cuitat D, Esquerda J, McArdle JJ, Olivera BM, Prevette D, Teichert RW. The rescue of developing avian motoneurons from programmed cell death by a selective inhibitor of the fetal muscle‐specific nicotinic acetylcholine receptor. Dev Neurobiol 68: 972‐980, 2008.
 330.Oppenheim RW, Houenou LJ, Parsadanian AS, Prevette D, Snider WD, Shen L. Glial cell line‐derived neurotrophic factor and developing mammalian motoneurons: Regulation of programmed cell death among motoneuron subtypes. J Neurosci 20: 5001‐5011, 2000.
 331.Oppenheim RW, Nunez R. Electrical stimulation of hindlimb increases neuronal cell death in chick embryo. Nature 295: 57‐59, 1982.
 332.Oppenheim RW, Prevette D, D'Costa A, Wang S, Houenou LJ, McIntosh JM. Reduction of neuromuscular activity is required for the rescue of motoneurons from naturally occurring cell death by nicotinic‐blocking agents. J Neurosci 20: 6117‐6124, 2000.
 333.Oppenheim RW, Prevette D, Houenou LJ, Pincon‐Raymond M, Dimitriadou V, Donevan A, O'Donovan M, Wenner P, McKemy DD, Allen PD. Neuromuscular development in the avian paralytic mutant crooked neck dwarf (cn/cn): Further evidence for the role of neuromuscular activity in motoneuron survival. J Comp Neurol 381: 353‐372, 1997.
 334.Oppenheim RW, Prevette D, Qin‐Wei Y, Collins F, MacDonald J. Control of embryonic motoneuron survival in vivo by ciliary neurotrophic factor. Science 251: 1616‐1618, 1991.
 335.Ottenheijm CA, Heunks LM, Dekhuijzen RP. Diaphragm adaptations in patients with COPD. Respir Res 9: 12, 2008.
 336.Owe JF, Daltveit AK, Gilhus NE. Causes of death among patients with myasthenia gravis in Norway between 1951 and 2001. J Neurol Neurosurg Psychiatry 77: 203‐207, 2006.
 337.Padua L, Tonali P, Aprile I, Caliandro P, Bartoccioni E, Evoli A. Seronegative myasthenia gravis: Comparison of neurophysiological picture in MuSK+ and MuSK‐ patients. Eur J Neurol 13: 273‐276, 2006.
 338.Palay SL. Synapses in the central nervous system. J Biophys Biochem Cytol 2: 193‐202, 1956.
 339.Pannuzzo M, Grassi A, Raudino A. Hydrodynamic enhancement of the diffusion rate in the region between two fluctuating membranes in close opposition: A theoretical and computational study. J Phys Chem B 118: 8662‐8672, 2014.
 340.Pearse BM. Clathrin: A unique protein associated with intracellular transfer of membrane by coated vesicles. Proc Natl Acad Sci U S A 73: 1255‐1259, 1976.
 341.Pehar M, Cassina P, Vargas MR, Castellanos R, Viera L, Beckman JS, Estevez AG, Barbeito L. Astrocytic production of nerve growth factor in motor neuron apoptosis: Implications for amyotrophic lateral sclerosis. J Neurochem 89: 464‐473, 2004.
 342.Perez V, Bermedo‐Garcia F, Zelada D, Court FA, Perez MA, Fuenzalida M, Abrigo J, Cabello‐Verrugio C, Moya‐Alvarado G, Tapia JC, Valenzuela V, Hetz C, Bronfman FC, Henriquez JP. The p75(NTR) neurotrophin receptor is required to organize the mature neuromuscular synapse by regulating synaptic vesicle availability. Acta Neuropathol Commun 7: 147, 2019.
 343.Perez‐Garcia MJ, Burden SJ. Increasing MuSK activity delays denervation and improves motor function in ALS mice. Cell Rep 2: 497‐502, 2012.
 344.Personius KE, Balice‐Gordon RJ. Activity‐dependent editing of neuromuscular synaptic connections. Brain Res Bull 53: 513‐522, 2000.
 345.Pittman R, Oppenheim RW. Cell death of motoneurons in the chick embryo spinal cord. IV. Evidence that a functional neuromuscular interaction is involved in the regulation of naturally occurring cell death and the stabilization of synapses. J Comp Neurol 187: 425‐446, 1979.
 346.Plomp JJ, Morsch M, Phillips WD, Verschuuren JJ. Electrophysiological analysis of neuromuscular synaptic function in myasthenia gravis patients and animal models. Exp Neurol 270: 41‐54, 2015.
 347.Plomp JJ, Van Kempen GT, De Baets MB, Graus YM, Kuks JB, Molenaar PC. Acetylcholine release in myasthenia gravis: Regulation at single end‐plate level. Ann Neurol 37: 627‐636, 1995.
 348.Plomp JJ, van Kempen GT, Molenaar PC. Adaptation of quantal content to decreased postsynaptic sensitivity at single endplates in alpha‐bungarotoxin‐treated rats. J Physiol 458: 487‐499, 1992.
 349.Prakash YS, Fournier M, Sieck GC. Effects of prenatal undernutrition on developing rat diaphragm. J Appl Physiol 75: 1044‐1052, 1993.
 350.Prakash YS, Gosselin LE, Zhan WZ, Sieck GC. Alterations of diaphragm neuromuscular junctions with hypothyroidism. J Appl Physiol 81: 1240‐1248, 1996.
 351.Prakash YS, Mantilla CB, Zhan WZ, Smithson KG, Sieck GC. Phrenic motoneuron morphology during rapid diaphragm muscle growth. J Appl Physiol 89: 563‐572, 2000.
 352.Prakash YS, Miller SM, Huang M, Sieck GC. Morphology of diaphragm neuromuscular junctions on different fibre types. J Neurocytol 25: 88‐100, 1996.
 353.Prakash YS, Miyata H, Zhan WZ, Sieck GC. Inactivity‐induced remodeling of neuromuscular junctions in rat diaphragmatic muscle. Muscle Nerve 22: 307‐319, 1999.
 354.Prakash YS, Sieck GC. Age‐related remodeling of neuromuscular junctions on type‐identified diaphragm fibers. Muscle Nerve 21: 887‐895, 1998.
 355.Prakash YS, Smithson KG, Sieck GC. Measurements of phrenic motoneuron somal volumes using laser scanning confocal microscopy: Comparisons with estimates using the Cavalieri principle the nucleator. Neurosci Abstr 19: 1112, 1993.
 356.Prakash YS, Smithson KG, Sieck GC. Growth‐related alterations in motor endplates of type‐identified diaphragm muscle fibres. J Neurocytol 24: 225‐235, 1995.
 357.Prakash YS, Zhan WZ, Miyata H, Sieck GC. Adaptations of diaphragm neuromuscular junction following inactivity. Acta Anat 154: 147‐161, 1995.
 358.Pun S, Sigrist M, Santos AF, Ruegg MA, Sanes JR, Jessell TM, Arber S, Caroni P. An intrinsic distinction in neuromuscular junction assembly and maintenance in different skeletal muscles. Neuron 34: 357‐370, 2002.
 359.Punga AR, Lin S, Oliveri F, Meinen S, Ruegg MA. Muscle‐selective synaptic disassembly and reorganization in MuSK antibody positive MG mice. Exp Neurol 230: 207‐217, 2011.
 360.Qaisar R, Bhaskaran S, Ranjit R, Sataranatarajan K, Premkumar P, Huseman K, Van Remmen H. Restoration of SERCA ATPase prevents oxidative stress‐related muscle atrophy and weakness. Redox Biol 20: 68‐74, 2019.
 361.Qaisar R, Pharaoh G, Bhaskaran S, Xu H, Ranjit R, Bian J, Ahn B, Georgescu C, Wren JD, Van Remmen H. Restoration of sarcoplasmic reticulum Ca(2+) ATPase (SERCA) activity prevents age‐related muscle atrophy and weakness in mice. Int J Mol Sci 22: 37, 2020.
 362.Raja MK, Preobraschenski J, Del Olmo‐Cabrera S, Martinez‐Turrillas R, Jahn R, Perez‐Otano I, Wesseling JF. Elevated synaptic vesicle release probability in synaptophysin/gyrin family quadruple knockouts. elife 8: e40744, 2019.
 363.Rathish D, Karalliyadda M. Takotsubo syndrome in patients with myasthenia gravis: A systematic review of previously reported cases. BMC Neurol 19: 281, 2019.
 364.Reddy LV, Koirala S, Sugiura Y, Herrera AA, Ko CP. Glial cells maintain synaptic structure and function and promote development of the neuromuscular junction in vivo. Neuron 40: 563‐580, 2003.
 365.Redfern P. Neuromuscular transmission in new‐born rats. J Physiol 209: 701‐709, 1970.
 366.Reid B, Slater CR, Bewick GS. Synaptic vesicle dynamics in rat fast and slow motor nerve terminals. J Neurosci 19: 2511‐2521, 1999.
 367.Reim K, Mansour M, Varoqueaux F, McMahon HT, Sudhof TC, Brose N, Rosenmund C. Complexins regulate a late step in Ca2+‐dependent neurotransmitter release. Cell 104: 71‐81, 2001.
 368.Reist NE, Smith SJ. Neurally evoked calcium transients in terminal Schwann cells at the neuromuscular junction. Proc Natl Acad Sci U S A 89: 7625‐7629, 1992.
 369.Rhodes SJ, Konieczny SF. Identification of MRF4: A new member of the muscle regulatory factor gene family. Genes Dev 3: 2050‐2061, 1989.
 370.Richards DA, Guatimosim C, Rizzoli SO, Betz WJ. Synaptic vesicle pools at the frog neuromuscular junction. Neuron 39: 529‐541, 2003.
 371.Richman DP, Gomez CM, Berman PW, Burres SA, Fitch FW, Arnason BG. Monoclonal anti‐acetylcholine receptor antibodies can cause experimental myasthenia. Nature 286: 738‐739, 1980.
 372.Richman DP, Nishi K, Morell SW, Chang JM, Ferns MJ, Wollmann RL, Maselli RA, Schnier J, Agius MA. Acute severe animal model of anti‐muscle‐specific kinase myasthenia: Combined postsynaptic and presynaptic changes. Arch Neurol 69: 453‐460, 2012.
 373.Riethmacher D, Sonnenberg‐Riethmacher E, Brinkmann V, Yamaai T, Lewin GR, Birchmeier C. Severe neuropathies in mice with targeted mutations in the ErbB3 receptor. Nature 389: 725‐730, 1997.
 374.Rizzoli SO, Betz WJ. The structural organization of the readily releasable pool of synaptic vesicles. Science 303: 2037‐2039, 2004.
 375.Rizzoli SO, Betz WJ. Synaptic vesicle pools. Nat Rev Neurosci 6: 57‐69, 2005.
 376.Rizzoli SO, Jahn R. Kiss‐and‐run, collapse and ‘readily retrievable’ vesicles. Traffic 8: 1137‐1144, 2007.
 377.Rizzoli SO, Richards DA, Betz WJ. Monitoring synaptic vesicle recycling in frog motor nerve terminals with FM dyes. J Neurocytol 32: 539‐549, 2003.
 378.Robbins N. Compensatory plasticity of aging at the neuromuscular junction. Exp Gerontol 27: 75‐81, 1992.
 379.Robbins N, Fahim MA. Progression of age changes in mature mouse motor nerve terminals and its relation to locomotor activity. J Neurocytol 14: 1019‐1036, 1985.
 380.Robitaille R. Purinergic receptors and their activation by endogenous purines at perisynaptic glial cells of the frog neuromuscular junction. J Neurosci 15: 7121‐7131, 1995.
 381.Robitaille R. Modulation of synaptic efficacy and synaptic depression by glial cells at the frog neuromuscular junction. Neuron 21: 847‐855, 1998.
 382.Robitaille R, Adler EM, Charlton MP. Strategic location of calcium channels at transmitter release sites of frog neuromuscular synapses. Neuron 5: 773‐779, 1990.
 383.Robitaille R, Garcia ML, Kaczorowski GJ, Charlton MP. Functional colocalization of calcium and calcium‐gated potassium channels in control of transmitter release. Neuron 11: 645‐655, 1993.
 384.Rocha MC, Pousinha PA, Correia AM, Sebastiao AM, Ribeiro JA. Early changes of neuromuscular transmission in the SOD1(G93A) mice model of ALS start long before motor symptoms onset. PLoS One 8: e73846, 2013.
 385.Roche SL, Sherman DL, Dissanayake K, Soucy G, Desmazieres A, Lamont DJ, Peles E, Julien JP, Wishart TM, Ribchester RR, Brophy PJ, Gillingwater TH. Loss of glial neurofascin155 delays developmental synapse elimination at the neuromuscular junction. J Neurosci 34: 12904‐12918, 2014.
 386.Rochon D, Rousse I, Robitaille R. Synapse‐glia interactions at the mammalian neuromuscular junction. J Neurosci 21: 3819‐3829, 2001.
 387.Rome S, Forterre A, Mizgier ML, Bouzakri K. Skeletal muscle‐released extracellular vesicles: State of the art. Front Physiol 10: 929, 2019.
 388.Rosenheimer JL, Smith DO. Differential changes in the endplate architecture of functionally diverse muscles during aging. J Neurophysiol 53: 1567‐1581, 1985.
 389.Rowley KL, Mantilla CB, Ermilov LG, Sieck GC. Synaptic vesicle distribution and release at rat diaphragm neuromuscular junctions. J Neurophysiol 98: 478‐487, 2007.
 390.Ruegsegger C, Maharjan N, Goswami A, Filezac de L'Etang A, Weis J, Troost D, Heller M, Gut H, Saxena S. Aberrant association of misfolded SOD1 with Na(+)/K(+)ATPase‐alpha3 impairs its activity and contributes to motor neuron vulnerability in ALS. Acta Neuropathol 131: 427‐451, 2016.
 391.Ruff RL. Sodium channel slow inactivation and the distribution of sodium channels on skeletal muscle fibres enable the performance properties of different skeletal muscle fibre types. Acta Physiol Scand 156: 159‐168, 1996.
 392.Ruff RL. Endplate contributions to the safety factor for neuromuscular transmission. Muscle Nerve 44: 854‐861, 2011.
 393.Ruff RL, Lennon VA. How myasthenia gravis alters the safety factor for neuromuscular transmission. J Neuroimmunol 201‐202: 13‐20, 2008.
 394.Ruiz R, Cano R, Casanas JJ, Gaffield MA, Betz WJ, Tabares L. Active zones and the readily releasable pool of synaptic vesicles at the neuromuscular junction of the mouse. J Neurosci 31: 2000‐2008, 2011.
 395.Ryu JK, Min D, Rah SH, Kim SJ, Park Y, Kim H, Hyeon C, Kim HM, Jahn R, Yoon TY. Spring‐loaded unraveling of a single SNARE complex by NSF in one round of ATP turnover. Science 347: 1485‐1489, 2015.
 396.Sabatini BL, Regehr WG. Timing of neurotransmission at fast synapses in the mammalian brain. Nature 384: 170‐172, 1996.
 397.Saied Z, Rachdi A, Thamlaoui S, Nabli F, Jeridi C, Baffoun N, Kaddour C, Belal S, Ben SS. Myasthenia gravis and COVID‐19: A case series and comparison with literature. Acta Neurol Scand 144 (3): 334‐340, 2021.
 398.Salanova M, Schiffl G, Blottner D. Atypical fast SERCA1a protein expression in slow myofibers and differential S‐nitrosylation prevented by exercise during long term bed rest. Histochem Cell Biol 132: 383‐394, 2009.
 399.Salpeter MM, Elderfrawi ME. Sizes of end plate compartments, densities of acetylcholine receptor and other quantitative aspects of neuromuscular transmission. J Histochem Cytochem 21: 769‐778, 1973.
 400.Sancho S, Young P, Suter U. Regulation of Schwann cell proliferation and apoptosis in PMP22‐deficient mice and mouse models of Charcot‐Marie‐Tooth disease type 1A. Brain 124: 2177‐2187, 2001.
 401.Sandow A. Fundamental mechanics of skeletal muscle contraction. Am J Phys Med 31: 103‐125, 1952.
 402.Sandrock AW Jr, Dryer SE, Rosen KM, Gozani SN, Kramer R, Theill LE, Fischbach GD. Maintenance of acetylcholine receptor number by neuregulins at the neuromuscular junction in vivo. Science 276: 599‐603, 1997.
 403.Sanes JR, Lichtman JW. Development of the vertebrate neuromuscular junction. Annu Rev Neurosci 22: 389‐442, 1999.
 404.Sanes JR, Lichtman JW. Induction, assembly, maturation and maintenance of a postsynaptic apparatus. Nat Rev Neurosci 2: 791‐805, 2001.
 405.Sanes JR, Marshall LM, McMahan UJ. Reinnervation of muscle fiber basal lamina after removal of myofibers. Differentiation of regenerating axons at original synaptic sites. J Cell Biol 78: 176‐198, 1978.
 406.Saroussi S, Nelson N. The little we know on the structure and machinery of V‐ATPase. J Exp Biol 212: 1604‐1610, 2009.
 407.Schiaffino S, Ausoni S, Gorza L, Saggin I, Gundersen K, Lomo T. Myosin heavy chain isoforms and velocity of shortening of type 2 skeletal muscle fibres. Acta Physiol Scand 134: 575‐576, 1988.
 408.Schiaffino S, Gorza L, Ausoni S. Muscle fiber types expressing different myosin heavy chain isoforms. Their functional properties and adaptive capacity. In: Pette D, editor. The Dynamic State of Muscle Fibers. Berlin: De Gruyter, 1990, p. 329‐341.
 409.Schikorski T, Stevens CF. Quantitative ultrastructural analysis of hippocampal excitatory synapses. J Neurosci 17: 5858‐5867, 1997.
 410.Schleiden MJ. Beitrage zur Phytogenesis. Arch Anat Physiol Wiss Med: 137‐176, 1838.
 411.Schwann T, Hünseler F. Mikroskopische Untersuchungen über die Ubereinstimmung in der Struktur und dem Wachstume der Tiere und Pflanzen. W Engelmann 176, 1910.
 412.Scurry AN, Heredia DJ, Feng CY, Gephart GB, Hennig GW, Gould TW. Structural and functional abnormalities of the neuromuscular junction in the Trembler‐J homozygote mouse model of congenital hypomyelinating neuropathy. J Neuropathol Exp Neurol 75: 334‐346, 2016.
 413.Seeburger JL, Tarras S, Natter H, Springer JE. Spinal cord motoneurons express p75NGFR and p145trkB mRNA in amyotrophic lateral sclerosis. Brain Res 621: 111‐115, 1993.
 414.Segal JR, Ceccarelli B, Fesce R, Hurlbut WP. Miniature endplate potential frequency and amplitude determined by an extension of Campbell's theorem. Biophys J 47: 183‐202, 1985.
 415.Seven YB, Mantilla CB, Sieck GC. Recruitment of rat diaphragm motor units across motor behaviors with different levels of diaphragm activation. J Appl Physiol 117: 1308‐1316, 2014.
 416.Seven YB, Mantilla CB, Zhan WZ, Sieck GC. Frequency‐domain analysis of diaphragm muscle EMG activity across ventilatory and non‐ventilatory motor behaviors. FASEB J 25: 1111.1124, 2011.
 417.Seyfarth EA. Julius Bernstein (1839‐1917): Pioneer neurobiologist and biophysicist. Biol Cybern 94: 2‐8, 2006.
 418.Shaw PJ, Chinnery RM, Thagesen H, Borthwick GM, Ince PG. Immunocytochemical study of the distribution of the free radical scavenging enzymes Cu/Zn superoxide dismutase (SOD1); MN superoxide dismutase (MN SOD) and catalase in the normal human spinal cord and in motor neuron disease. J Neurol Sci 147: 115‐125, 1997.
 419.Shi L, Shen QT, Kiel A, Wang J, Wang HW, Melia TJ, Rothman JE, Pincet F. SNARE proteins: One to fuse and three to keep the nascent fusion pore open. Science 335: 1355‐1359, 2012.
 420.Shortt CM, Fredsted A, Bradford A, O'Halloran KD. Diaphragm muscle remodeling in a rat model of chronic intermittent hypoxia. J Histochem Cytochem 61: 487‐499, 2013.
 421.Shrivastava AN, Redeker V, Fritz N, Pieri L, Almeida LG, Spolidoro M, Liebmann T, Bousset L, Renner M, Lena C, Aperia A, Melki R, Triller A. alpha‐synuclein assemblies sequester neuronal alpha3‐Na+/K+‐ATPase and impair Na+ gradient. EMBO J 34: 2408‐2423, 2015.
 422.Sieb JP. Myasthenia gravis: An update for the clinician. Clin Exp Immunol 175: 408‐418, 2014.
 423.Sieck GC. Neural control of the inspiratory pump. NIPS 6: 260‐264, 1991.
 424.Sieck GC. Physiological effects of diaphragm muscle denervation and disuse. Clin Chest Med 15: 641‐659, 1994.
 425.Sieck GC, Ferreira LF, Reid MB, Mantilla CB. Mechanical properties of respiratory muscles. Compr Physiol 3: 1553‐1567, 2013.
 426.Sieck GC, Fournier M. Diaphragm motor unit recruitment during ventilatory and nonventilatory behaviors. J Appl Physiol 66: 2539‐2545, 1989.
 427.Sieck GC, Fournier M, Enad JG. Fiber type composition of muscle units in the cat diaphragm. Neurosci Lett 97: 29‐34, 1989.
 428.Sieck GC, Han YS, Prakash YS, Jones KA. Cross‐bridge cycling kinetics, actomyosin ATPase activity and myosin heavy chain isoforms in skeletal and smooth respiratory muscle. Comp Biochem Physiol 119: 435‐450, 1997.
 429.Sieck GC, Prakash YS. Fatigue at the neuromuscular junction: Branch point vs. presynaptic vs. postsynaptic mechanisms. In: Stuart DG, Gandevia S, Enoka RM, McComas AJ, Thomas CK, editors. Neural and Neuromuscular Aspects of Muscle Fatigue. New York, NY: Plenum Press, 1995, p. 83‐100.
 430.Sieck GC, Van Balkom RH, Prakash YS, Zhan WZ, Dekhuijzen PN. Corticosteroid effects on diaphragm neuromuscular junctions. J Appl Physiol 86: 114‐122, 1999.
 431.Sieck GC, Zhan WZ, Prakash YS, Daood MJ, Watchko JF. SDH and actomyosin ATPase activities of different fiber types in rat diaphragm muscle. J Appl Physiol 79: 1629‐1639, 1995.
 432.Slater CR. Postnatal maturation of nerve‐muscle junctions in hindlimb muscles of the mouse. Dev Biol 94: 11‐22, 1982.
 433.Slater CR. The functional organization of motor nerve terminals. Prog Neurobiol 134: 55‐103, 2015.
 434.Slater CR. The structure of human neuromuscular junctions: Some unanswered molecular questions. Int J Mol Sci 18: 2183, 2017.
 435.Slater CR, Lyons PR, Walls TJ, Fawcett PR, Young C. Structure and function of neuromuscular junctions in the vastus lateralis of man. A motor point biopsy study of two groups of patients. Brain 115 (Pt 2): 451‐478, 1992.
 436.Smith DO, Chapman MR. Acetylcholine receptor binding properties at the rat neuromuscular junction during aging. J Neurochem 48: 1834‐1841, 1987.
 437.Smith DO, Williams KD, Emmerling M. Changes in acetylcholine receptor distribution and binding properties at the neuromuscular junction during aging. Int J Dev Neurosci 8: 629‐642, 1990.
 438.Smith IW, Mikesh M, Lee Y, Thompson WJ. Terminal Schwann cells participate in the competition underlying neuromuscular synapse elimination. J Neurosci 33: 17724‐17736, 2013.
 439.Soendenbroe C, Heisterberg MF, Schjerling P, Karlsen A, Kjaer M, Andersen JL, Mackey AL. Molecular indicators of denervation in aging human skeletal muscle. Muscle Nerve 60: 453‐463, 2019.
 440.Sole G, Mathis S, Friedman D, Salort‐Campana E, Tard C, Bouhour F, Magot A, Annane D, Clair B, Le Masson G, Soulages A, Duval F, Carla L, Violleau MH, Saulnier T, Segovia‐Kueny S, Kern L, Antoine JC, Beaudonnet G, Audic F, Kremer L, Chanson JB, Nadaj‐Pakleza A, Stojkovic T, Cintas P, Spinazzi M, Foubert‐Samier A, Attarian S. Impact of coronavirus disease 2019 in a French cohort of myasthenia gravis. Neurology 96 (16): e2109‐e2120, 2021.
 441.Sotelo C. Camillo Golgi and Santigo Ramon y Cajal: The anatomical organization of the cortex of the cerebellum. Can the neuron doctrine still support our actual knowledge on the cerebellar structural arrangement? Brain Res Rev 66 (1–2): 16‐34, 2011.
 442.Soykan T, Maritzen T, Haucke V. Modes and mechanisms of synaptic vesicle recycling. Curr Opin Neurobiol 39: 17‐23, 2016.
 443.Sterz R, Pagala M, Peper K. Postjunctional characteristics of the endplates in mammalian fast and slow muscles. Pflugers Arch 398: 48‐54, 1983.
 444.Steyn FJ, Lee K, Fogarty MJ, Veldhuis JD, McCombe PA, Bellingham MC, Ngo ST, Chen C. Growth hormone secretion is correlated with neuromuscular innervation rather than motor neuron number in early‐symptomatic male amyotrophic lateral sclerosis mice. Endocrinology 154: 4695‐4706, 2013.
 445.Stockbridge N. Differential conduction at axonal bifurcations. II. Theoretical basis. J Neurophysiol 59: 1286‐1295, 1988.
 446.Stockbridge N, Stockbridge LL. Differential conduction at axonal bifurcations. I. Effect of electrotonic length. J Neurophysiol 59: 1277‐1285, 1988.
 447.Stryker E, Johnson KG. LAR, liprin alpha and the regulation of active zone morphogenesis. J Cell Sci 120: 3723‐3728, 2007.
 448.Sudhof TC. The synaptic vesicle cycle. Annu Rev Neurosci 27: 509‐547, 2004.
 449.Sudhof TC. Neurotransmitter release: The last millisecond in the life of a synaptic vesicle. Neuron 80: 675‐690, 2013.
 450.Szule JA, Jung JH, McMahan UJ. The structure and function of 'active zone material' at synapses. Philos Trans R Soc Lond Ser B Biol Sci 370: 20140189, 2015.
 451.Taetzsch T, Tenga MJ, Valdez G. Muscle fibers secrete FGFBP1 to slow degeneration of neuromuscular synapses during aging and progression of ALS. J Neurosci 37: 70‐82, 2017.
 452.Takamori M. Myasthenia gravis: From the viewpoint of pathogenicity focusing on acetylcholine receptor clustering, trans‐synaptic homeostasis and synaptic stability. Front Mol Neurosci 13: 86, 2020.
 453.Takamori S, Holt M, Stenius K, Lemke EA, Gronborg M, Riedel D, Urlaub H, Schenck S, Brugger B, Ringler P, Muller SA, Rammner B, Grater F, Hub JS, De Groot BL, Mieskes G, Moriyama Y, Klingauf J, Grubmuller H, Heuser J, Wieland F, Jahn R. Molecular anatomy of a trafficking organelle. Cell 127: 831‐846, 2006.
 454.Takeuchi A. Junctional transmission I. Postsynaptic mechanisms. Compr Physiol: 295‐327, 2011.
 455.Talmadge RJ, Roy RR, Bodine‐Fowler SC, Pierotti DJ, Edgerton VR. Adaptations in myosin heavy chain profile in chronically unloaded muscles. Basic Appl Myol 5: 117‐137, 1995.
 456.Tanaka H, Furuya T, Kameda N, Kobayashi T, Mizusawa H. Triad proteins and intracellular Ca2+ transients during development of human skeletal muscle cells in aneural and innervated cultures. J Muscle Res Cell Motil 21: 507‐526, 2000.
 457.Tang J, Landmesser L. Reduction of intramuscular nerve branching and synaptogenesis is correlated with decreased motoneuron survival. J Neurosci 13: 3095‐3103, 1993.
 458.Tansey EM. Henry Dale and the discovery of acetylcholine. C R Biol 329: 419‐425, 2006.
 459.Tapia JC, Wylie JD, Kasthuri N, Hayworth KJ, Schalek R, Berger DR, Guatimosim C, Seung HS, Lichtman JW. Pervasive synaptic branch removal in the mammalian neuromuscular system at birth. Neuron 74: 816‐829, 2012.
 460.Taxt T. Local and systemic effects of tetrodotoxin on the formation and elimination of synapses in reinnervated adult rat muscle. J Physiol 340: 175‐194, 1983.
 461.Thomas MM, Khan W, Betik AC, Wright KJ, Hepple RT. Initiating exercise training in late middle age minimally protects muscle contractile function and increases myocyte oxidative damage in senescent rats. Exp Gerontol 45: 856‐867, 2010.
 462.Thompson CB, McDonough AA. Skeletal muscle Na, K‐ATPase alpha and beta subunit protein levels respond to hypokalemic challenge with isoform and muscle type specificity. J Biol Chem 271: 32653‐32658, 1996.
 463.Thompson DM, Buettner HM. Neurite outgrowth is directed by schwann cell alignment in the absence of other guidance cues. Ann Biomed Eng 34: 161‐168, 2006.
 464.Thompson W. Synapse elimination in neonatal rat muscle is sensitive to pattern of muscle use. Nature 302: 614‐616, 1983.
 465.Todd KJ, Darabid H, Robitaille R. Perisynaptic glia discriminate patterns of motor nerve activity and influence plasticity at the neuromuscular junction. J Neurosci 30: 11870‐11882, 2010.
 466.Tokumaru H, Umayahara K, Pellegrini LL, Ishizuka T, Saisu H, Betz H, Augustine GJ, Abe T. SNARE complex oligomerization by synaphin/complexin is essential for synaptic vesicle exocytosis. Cell 104: 421‐432, 2001.
 467.Tomlinson BE, Irving D. The numbers of limb motor neurons in the human lumbosacral cord throughout life. J Neurol Sci 34: 213‐219, 1977.
 468.Tong JJ. Mitochondrial delivery is essential for synaptic potentiation. Biol Bull 212: 169‐175, 2007.
 469.Trachtenberg JT, Thompson WJ. Nerve terminal withdrawal from rat neuromuscular junctions induced by neuregulin and Schwann cells. J Neurosci 17: 6243‐6255, 1997.
 470.Trelease RB, Sieck GC, Harper RM. A new technique for acute and chronic recording of crural diaphragm EMG in cats. Electroencephalogr Clin Neurophysiol 53: 459‐462, 1982.
 471.Tremblay E, Martineau E, Robitaille R. Opposite synaptic alterations at the neuromuscular junction in an ALS mouse model: When motor units matter. J Neurosci 37: 8901‐8918, 2017.
 472.Trinidad JC, Fischbach GD, Cohen JB. The Agrin/MuSK signaling pathway is spatially segregated from the neuregulin/ErbB receptor signaling pathway at the neuromuscular junction. J Neurosci 20: 8762‐8770, 2000.
 473.Turner MR, Hardiman O, Benatar M, Brooks BR, Chio A, de Carvalho M, Ince PG, Lin C, Miller RG, Mitsumoto H, Nicholson G, Ravits J, Shaw PJ, Swash M, Talbot K, Traynor BJ, Van den Berg LH, Veldink JH, Vucic S, Kiernan MC. Controversies and priorities in amyotrophic lateral sclerosis. Lancet Neurol 12: 310‐322, 2013.
 474.Van Hoecke A, Schoonaert L, Lemmens R, Timmers M, Staats KA, Laird AS, Peeters E, Philips T, Goris A, Dubois B, Andersen PM, Al‐Chalabi A, Thijs V, Turnley AM, van Vught PW, Veldink JH, Hardiman O, Van Den Bosch L, Gonzalez‐Perez P, Van Damme P, Brown RH Jr, van den Berg LH, Robberecht W. EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans. Nat Med 18: 1418‐1422, 2012.
 475.van Lunteren E, Moyer M, Kaminski HJ. Adverse effects of myasthenia gravis on rat phrenic diaphragm contractile performance. J Appl Physiol (1985) 97: 895‐901, 2004.
 476.Vanlandingham PA, Barmchi MP, Royer S, Green R, Bao H, Reist N, Zhang B. AP180 couples protein retrieval to clathrin‐mediated endocytosis of synaptic vesicles. Traffic 15: 433‐450, 2014.
 477.Vernon EM, Oppenheim RW, Johnson JE. Distinct muscle targets do not vary in the developmental regulation of brain‐derived neurotrophic factor. J Comp Neurol 470: 330‐337, 2004.
 478.Viana Di Prisco G. Hebb synaptic plasticity. Prog Neurobiol 22: 89‐102, 1984.
 479.Vila L, Barrett EF, Barrett JN. Stimulation‐induced mitochondrial [Ca2+] elevations in mouse motor terminals: Comparison of wild‐type with SOD1‐G93A. J Physiol 549: 719‐728, 2003.
 480.Vilmont V, Cadot B, Vezin E, Le Grand F, Gomes ER. Dynein disruption perturbs post‐synaptic components and contributes to impaired MuSK clustering at the NMJ: Implication in ALS. Sci Rep 6: 27804, 2016.
 481.Vock VM, Ponomareva ON, Rimer M. Evidence for muscle‐dependent neuromuscular synaptic site determination in mammals. J Neurosci 28: 3123‐3130, 2008.
 482.Vos M, Lauwers E, Verstreken P. Synaptic mitochondria in synaptic transmission and organization of vesicle pools in health and disease. Front Synaptic Neurosci 2: 139, 2010.
 483.Wainger BJ, Macklin EA, Vucic S, McIlduff CE, Paganoni S, Maragakis NJ, Bedlack R, Goyal NA, Rutkove SB, Lange DJ, Rivner MH, Goutman SA, Ladha SS, Mauricio EA, Baloh RH, Simmons Z, Pothier L, Kassis SB, La T, Hall M, Evora A, Klements D, Hurtado A, Pereira JD, Koh J, Celnik PA, Chaudhry V, Gable K, Juel VC, Phielipp N, Marei A, Rosenquist P, Meehan S, Oskarsson B, Lewis RA, Kaur D, Kiskinis E, Woolf CJ, Eggan K, Weiss MD, Berry JD, David WS, Davila‐Perez P, Camprodon JA, Pascual‐Leone A, Kiernan MC, Shefner JM, Atassi N, Cudkowicz ME. Effect of ezogabine on cortical and spinal motor neuron excitability in amyotrophic lateral sclerosis: A randomized clinical trial. JAMA Neurol 78: 186‐196, 2021.
 484.Walrond JP, Reese TS. Structure of axon terminals and active zones at synapses on lizard twitch and tonic muscle fibers. J Neurosci 5: 1118‐1131, 1985.
 485.Wernig A, Herrera AA. Sprouting and remodelling at the nerve‐muscle junction. Prog Neurobiol 27: 251‐291, 1986.
 486.Westerberg E, Punga AR. Mortality rates and causes of death in Swedish myasthenia gravis patients. Neuromuscul Disord 30: 815‐824, 2020.
 487.Whelchel DD, Brehmer TM, Brooks PM, Darragh N, Coffield JA. Molecular targets of botulinum toxin at the mammalian neuromuscular junction. Mov Disord 19 (Suppl 8): S7‐S16, 2004.
 488.Willadt S, Nash M, Slater CR. Age‐related fragmentation of the motor endplate is not associated with impaired neuromuscular transmission in the mouse diaphragm. Sci Rep 6: 24849, 2016.
 489.Williams AH, Liu N, van Rooij E, Olson EN. MicroRNA control of muscle development and disease. Curr Opin Cell Biol 21: 461‐469, 2009.
 490.Williams AH, Valdez G, Moresi V, Qi X, McAnally J, Elliott JL, Bassel‐Duby R, Sanes JR, Olson EN. MicroRNA‐206 delays ALS progression and promotes regeneration of neuromuscular synapses in mice. Science 326: 1549‐1554, 2009.
 491.Willshaw DJ. The establishment and the subsequent elimination of polyneuronal innervation of developing muscle: Theoretical considerations. Proc R Soc Lond B Biol Sci 212: 233‐252, 1981.
 492.Wong‐Riley MT. Cytochrome oxidase: An endogenous metabolic marker for neuronal activity. Trends Neurosci 12: 94‐101, 1989.
 493.Wood SJ, Slater CR. Safety factor at the neuromuscular junction. Prog Neurobiol 64: 393‐429, 2001.
 494.Wood SJS, C.R. Quantal content at neuromuscular junctions that lack postsynaptic folds. J Physiol Lond 511: 142P‐142P, 1998.
 495.Wray SH. Innervation ratios for large and small limb muscles in the baboon. J Comp Neurol 137: 227‐250, 1969.
 496.Wu J, Yan Z, Li Z, Qian X, Lu S, Dong M, Zhou Q, Yan N. Structure of the voltage‐gated calcium channel Ca(v)1.1 at 3.6 A resolution. Nature 537: 191‐196, 2016.
 497.Wu KD, Lytton J. Molecular cloning and quantification of sarcoplasmic reticulum Ca(2+)‐ATPase isoforms in rat muscles. Am J Phys 264: C333‐C341, 1993.
 498.Wu W, Li L, Yick LW, Chai H, Xie Y, Yang Y, Prevette DM, Oppenheim RW. GDNF and BDNF alter the expression of neuronal NOS, c‐Jun, and p75 and prevent motoneuron death following spinal root avulsion in adult rats. J Neurotrauma 20: 603‐612, 2003.
 499.Wuerker RB, McPhedran M, Henneman E. Properties of motor units in a heterogeneous pale muscle (M. gastrocnemius) of the cat. J Neurophysiol 28: 85‐99, 1965.
 500.Xu K, Jha S, Hoch W, Dryer SE. Delayed synapsing muscles are more severely affected in an experimental model of MuSK‐induced myasthenia gravis. Neuroscience 143: 655‐659, 2006.
 501.Yang DP, Zhang DP, Mak KS, Bonder DE, Pomeroy SL, Kim HA. Schwann cell proliferation during Wallerian degeneration is not necessary for regeneration and remyelination of the peripheral nerves: Axon‐dependent removal of newly generated Schwann cells by apoptosis. Mol Cell Neurosci 38: 80‐88, 2008.
 502.Yang X, Arber S, William C, Li L, Tanabe Y, Jessell TM, Birchmeier C, Burden SJ. Patterning of muscle acetylcholine receptor gene expression in the absence of motor innervation. Neuron 30: 399‐410, 2001.
 503.Yao C, Wang Q, Wang Y, Wu J, Cao X, Lu Y, Chen Y, Feng W, Gu X, Dun XP, Yu B. Loc680254 regulates Schwann cell proliferation through Psrc1 and Ska1 as a microRNA sponge following sciatic nerve injury. Glia 69: 2391‐2403, 2021.
 504.York AL, Zheng JQ. Super‐resolution microscopy reveals a nanoscale organization of acetylcholine receptors for trans‐synaptic alignment at neuromuscular synapses. eNeuro 4, 2017.
 505.Yoshihara T, Ishii T, Iwata M, Nomoto M. Ultrastructural and histochemical study of the motor end plates of the intrinsic laryngeal muscles in amyotrophic lateral sclerosis. Ultrastruct Pathol 22: 121‐126, 1998.
 506.Zahler R, Sun W, Ardito T, Zhang ZT, Kocsis JD, Kashgarian M. The alpha3 isoform protein of the Na+, K(+)‐ATPase is associated with the sites of cardiac and neuromuscular impulse transmission. Circ Res 78: 870‐879, 1996.
 507.Zajac FE, Faden JS. Relationship among recruitment order, axonal conduction velocity, and muscle‐unit properties of type‐identified motor units in cat plantaris muscle. J Neurophysiol 53 (5): 1303‐1322, 1985.
 508.Zengel JE, Reid SA, Sypert GW, Munson JB. Membrane electrical properties and prediction of motor‐unit type of medial gastrocnemius motoneurons in the cat. J Neurophysiol 53 (5): 1323‐1344, 1985.
 509.Zhan WZ, Mantilla CB, Sieck GC. Regulation of neuromuscular transmission by neurotrophins. Sheng Li Xue Bao 55: 617‐624, 2003.
 510.Zhang B, Koh YH, Beckstead RB, Budnik V, Ganetzky B, Bellen HJ. Synaptic vesicle size and number are regulated by a clathrin adaptor protein required for endocytosis. Neuron 21: 1465‐1475, 1998.
 511.Zhang L, Morris KJ, Ng YC. Fiber type‐specific immunostaining of the Na+, K+‐ATPase subunit isoforms in skeletal muscle: Age‐associated differential changes. Biochim Biophys Acta 1762: 783‐793, 2006.
 512.Zhu X, Lai C, Thomas S, Burden SJ. Neuregulin receptors, erbB3 and erbB4, are localized at neuromuscular synapses. EMBO J 14: 5842‐5848, 1995.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Structure and Function of the Mammalian Neuromuscular Junction
 

How to Cite

Leah A. Davis, Matthew J. Fogarty, Alyssa Brown, Gary C. Sieck. Structure and Function of the Mammalian Neuromuscular Junction. Compr Physiol 2022, 12: 3731-3766. doi: 10.1002/cphy.c210022