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Maintenance and Regulation in Brain of Neurotransmission, Trophic Factors, and Immune Responses

Carl W. Cotman, Jennifer S. Kahle, Andrew R. Korotzer

10.1002/cphy.cp110113

Source: Supplement 28: Handbook of Physiology, Aging

Originally published: 1995

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 The Imbalance Hypothesis of Aging
2 Neurotransmitter Systems
2.1 Glutamate Receptors
2.2 GABA Receptors
2.3 Summary
3 Neurotrophic Factors
3.1 Nerve Growth Factor
3.2 Fibroblast Growth Factor
3.3 Cytokines as Neurotrophic Factors
4 The Immune System in the CNS
4.1 The Immune System and Alzheimer's Disease
4.2 Cytokines and the Immune System
5 Summary and Conclusions
Figure 1. Figure 1.

The NMDA receptor complex. The transmitter recognition site binds agonists such as NMDA, L‐glutamate, and L‐aspartate. This binding opens the ion channel, allowing Na+ and Ca2+ ions to flow inside the neuron and K+ ions to flow out. The glycine site allosterically modulates receptor function, probably by increasing the frequency of agonist‐induced channel opening. The NMDA‐receptor complex is also regulated by polyamines and Zn2+ at two other modulatory sites. At resting membrane potential, Mg2+ blocks the ion channel in a voltage‐dependent manner and this block is relieved during membrane depolarization. The ion channel also contains a phencyclidine (PCP) recognition site, which can bind PCP, ketamine, and MK‐801, serving to block the open channel.

Reprinted with permission from Ulas and Cotman 124
Figure 2. Figure 2.

Binding to NMDA receptors decreases with age in mice, normal human, and Alzheimer brain. A: Scatchard presentation of the specific binding of increasing concentrations of [3H]MK‐801 to fore‐brain homogenates of young and aged mice. B: Number of MK‐801 binding sites (Bmax) plotted against age shows that binding decreases with age in membranes prepared from human frontal cortex. Binding was done in the presence of glutamate and glycine. Linear correlation coefficient was r = −0.826, P < 0.001. C: Autoradiographical analysis showed that MK‐801 binding was decreased in the anterior hippocampus and parahippocampal gyrus in Alzheimer tissue. Binding was done in the presence of glutamate and glycine. GD out, outer two‐thirds of the dentate gyrus molecular layer; GD in, inner one‐third of the dentate gyrus molecular layer; infra, infragranular layer; PG in, inner layer of the parahippocampal gyrus; PG out, outer layer of the parahippocampal gyrus. *P < 0.05, **P < 0.01 (one‐way analysis of variance (ANOVA), Scheffe F test).

Reprinted with permission from A: Cohen and Müller 10; B: Piggott et al. 102; and C: Ulas et al. 125 (Pergamon Press Ltd, Headington Hill Hall, Oxford OX3 OBW, UK)
Figure 3. Figure 3.

Binding to the GABA receptor–coupled ionophore is reduced in aged rats, and CSF levels are reduced with age and in age‐related diseases in the human. A: Representative Scatchard plots show saturable, single‐binding components for [35S]t‐butyl‐bicyclophosphorothionate (TBPS) in cortical membranes from adult (180‐day‐old) and aged (800‐day‐old) rats. Note that affinity of binding (slope) did not change, whereas maximal number of binding sites (intersect at the x axis) was reduced in aged animals. Data are mean values of triplicates obtained in a representative experiment. Repeated experiments gave similar results. B: Human cerebrospinal fluid GABA concentration decreases with age. Circles represent data from males; squares, from females. Linear regression analysis showed significant negative correlation (r = −0.81, P < 0.01). Significant negative correlations were also found in men (r = −0.79, P < 0.01) and in women (r = −0.88, P < 0.01). C: Levels of GABA in CSF are reduced in various neurologic disorders and controls. Height of each bar represents mean (± SD). Numbers in parentheses represent number of cases. *P < 0.001 by Student's t test.

Reprinted with permission from A: Erdö and Wolff 26; B: Takayama et al. 121; and C: Manyam et al. 80 (copyright 1980, American Medical Association)
Figure 4. Figure 4.

NGF improves memory function in previously impaired aged rats on a memory task and reduces the degree of atrophy of cholinergic neurons in basal forebrain structures. A: Performance on a water maze test of three groups of aged rats (open triangle, aged nonimpaired; circle, aged impaired; closed triangle, NGF‐treated aged impaired) in test weeks 1 and 2, expressed as the time to reach the hidden platform (escape latency). A group of identically tested young (3‐month‐old) rats (square) has been included for comparison. Left panel, mean performance (± SEM) over all trials (*P < 0.025; +P < 0.01). Right panel, memory retention expressed as difference between mean performance in last 3 days of test week 1 and first test day of test week 2 (*P < 0.025; +P < 0.025). B: AChE‐positive cell body size for young rats and treated and untreated aged rats. Bars represent means (± SEM) of AChE‐positive cell body size given as cross‐sectional area in μm2 from striatum and nucleus basalis magnocellularis (NBM). *P < 0.01 compared to the noninfused (left) side; Student's related t test.

Reprinted with permission from Fischer et al. 30, copyright (1987) Macmillan Magazines Limited
Figure 5. Figure 5.

FGF‐2 (bFGF) infusion protects neurons from death after axotomy. The effect of intraventricular infusion (0.025 μg/h) of FGF‐2 for 14 days on the survival of layer II stellate cells in the entorhinal cortex after axotomy. Neurons ipsilateral and contralateral to the lesion were counted in bFGF infused animals 14 days post‐lesion (n = 6) and controls which received either saline infusion (n = 4) or no infusion (n = 5) at 14 days post‐lesion and controls at 30 days post‐lesion (n = 6). Additionally, cells in four naive unoperated animals were counted to insure there were no hemispheric differences in the entorhinal cortex. The percentage of cell survival (ipsilateral/contralateral ratios) was compared with a Student's t test. *P ≦ 0.005 from naive group; **P ≦ 0.005 from either control group.

Reprinted with permission from Cummings et al. 20
Figure 6. Figure 6.

FGF‐2 is present in the senile plaque environment. A: Diagram illustrating potential sites of FGF‐2 involvement in plaque formation and misdirected plasticity. B: FGF‐2 immunoreactivity detects senile plaques located in dentate gyrus molecular layer of Alzheimer brain (bar = 100 μm). C: Photomicrograph illustrating presence of FGF‐2‐immunoreactive astrocytes surrounding an FGF‐2‐immunore‐active senile plaque (bar = 10 μm).

Reprinted with permission from Cotman et al. 15
Figure 7. Figure 7.

Simplified mechanism by which cytokines may regulate neuronal plasticity following injury to CNS. Primed by the original insult, microglia start a cascade of processes leading to neuronal sprouting by the release of IL‐1. Glucocorticoids from the adrenal gland can regulate the molecular cascade by inhibiting microglial function.
Figure 8. Figure 8.

Clearance of debris is slower and synapse replacement incomplete after lesions in aged rats. Graphs illustrate reciprocal relationship between degeneration product removal and reappearance of normal synapses in both young and aged rats.

Reprinted with permission from Hoff et al. 57


Figure 1.

The NMDA receptor complex. The transmitter recognition site binds agonists such as NMDA, L‐glutamate, and L‐aspartate. This binding opens the ion channel, allowing Na+ and Ca2+ ions to flow inside the neuron and K+ ions to flow out. The glycine site allosterically modulates receptor function, probably by increasing the frequency of agonist‐induced channel opening. The NMDA‐receptor complex is also regulated by polyamines and Zn2+ at two other modulatory sites. At resting membrane potential, Mg2+ blocks the ion channel in a voltage‐dependent manner and this block is relieved during membrane depolarization. The ion channel also contains a phencyclidine (PCP) recognition site, which can bind PCP, ketamine, and MK‐801, serving to block the open channel.

Reprinted with permission from Ulas and Cotman 124


Figure 2.

Binding to NMDA receptors decreases with age in mice, normal human, and Alzheimer brain. A: Scatchard presentation of the specific binding of increasing concentrations of [3H]MK‐801 to fore‐brain homogenates of young and aged mice. B: Number of MK‐801 binding sites (Bmax) plotted against age shows that binding decreases with age in membranes prepared from human frontal cortex. Binding was done in the presence of glutamate and glycine. Linear correlation coefficient was r = −0.826, P < 0.001. C: Autoradiographical analysis showed that MK‐801 binding was decreased in the anterior hippocampus and parahippocampal gyrus in Alzheimer tissue. Binding was done in the presence of glutamate and glycine. GD out, outer two‐thirds of the dentate gyrus molecular layer; GD in, inner one‐third of the dentate gyrus molecular layer; infra, infragranular layer; PG in, inner layer of the parahippocampal gyrus; PG out, outer layer of the parahippocampal gyrus. *P < 0.05, **P < 0.01 (one‐way analysis of variance (ANOVA), Scheffe F test).

Reprinted with permission from A: Cohen and Müller 10; B: Piggott et al. 102; and C: Ulas et al. 125 (Pergamon Press Ltd, Headington Hill Hall, Oxford OX3 OBW, UK)


Figure 3.

Binding to the GABA receptor–coupled ionophore is reduced in aged rats, and CSF levels are reduced with age and in age‐related diseases in the human. A: Representative Scatchard plots show saturable, single‐binding components for [35S]t‐butyl‐bicyclophosphorothionate (TBPS) in cortical membranes from adult (180‐day‐old) and aged (800‐day‐old) rats. Note that affinity of binding (slope) did not change, whereas maximal number of binding sites (intersect at the x axis) was reduced in aged animals. Data are mean values of triplicates obtained in a representative experiment. Repeated experiments gave similar results. B: Human cerebrospinal fluid GABA concentration decreases with age. Circles represent data from males; squares, from females. Linear regression analysis showed significant negative correlation (r = −0.81, P < 0.01). Significant negative correlations were also found in men (r = −0.79, P < 0.01) and in women (r = −0.88, P < 0.01). C: Levels of GABA in CSF are reduced in various neurologic disorders and controls. Height of each bar represents mean (± SD). Numbers in parentheses represent number of cases. *P < 0.001 by Student's t test.

Reprinted with permission from A: Erdö and Wolff 26; B: Takayama et al. 121; and C: Manyam et al. 80 (copyright 1980, American Medical Association)


Figure 4.

NGF improves memory function in previously impaired aged rats on a memory task and reduces the degree of atrophy of cholinergic neurons in basal forebrain structures. A: Performance on a water maze test of three groups of aged rats (open triangle, aged nonimpaired; circle, aged impaired; closed triangle, NGF‐treated aged impaired) in test weeks 1 and 2, expressed as the time to reach the hidden platform (escape latency). A group of identically tested young (3‐month‐old) rats (square) has been included for comparison. Left panel, mean performance (± SEM) over all trials (*P < 0.025; +P < 0.01). Right panel, memory retention expressed as difference between mean performance in last 3 days of test week 1 and first test day of test week 2 (*P < 0.025; +P < 0.025). B: AChE‐positive cell body size for young rats and treated and untreated aged rats. Bars represent means (± SEM) of AChE‐positive cell body size given as cross‐sectional area in μm2 from striatum and nucleus basalis magnocellularis (NBM). *P < 0.01 compared to the noninfused (left) side; Student's related t test.

Reprinted with permission from Fischer et al. 30, copyright (1987) Macmillan Magazines Limited


Figure 5.

FGF‐2 (bFGF) infusion protects neurons from death after axotomy. The effect of intraventricular infusion (0.025 μg/h) of FGF‐2 for 14 days on the survival of layer II stellate cells in the entorhinal cortex after axotomy. Neurons ipsilateral and contralateral to the lesion were counted in bFGF infused animals 14 days post‐lesion (n = 6) and controls which received either saline infusion (n = 4) or no infusion (n = 5) at 14 days post‐lesion and controls at 30 days post‐lesion (n = 6). Additionally, cells in four naive unoperated animals were counted to insure there were no hemispheric differences in the entorhinal cortex. The percentage of cell survival (ipsilateral/contralateral ratios) was compared with a Student's t test. *P ≦ 0.005 from naive group; **P ≦ 0.005 from either control group.

Reprinted with permission from Cummings et al. 20


Figure 6.

FGF‐2 is present in the senile plaque environment. A: Diagram illustrating potential sites of FGF‐2 involvement in plaque formation and misdirected plasticity. B: FGF‐2 immunoreactivity detects senile plaques located in dentate gyrus molecular layer of Alzheimer brain (bar = 100 μm). C: Photomicrograph illustrating presence of FGF‐2‐immunoreactive astrocytes surrounding an FGF‐2‐immunore‐active senile plaque (bar = 10 μm).

Reprinted with permission from Cotman et al. 15


Figure 7.

Simplified mechanism by which cytokines may regulate neuronal plasticity following injury to CNS. Primed by the original insult, microglia start a cascade of processes leading to neuronal sprouting by the release of IL‐1. Glucocorticoids from the adrenal gland can regulate the molecular cascade by inhibiting microglial function.



Figure 8.

Clearance of debris is slower and synapse replacement incomplete after lesions in aged rats. Graphs illustrate reciprocal relationship between degeneration product removal and reappearance of normal synapses in both young and aged rats.

Reprinted with permission from Hoff et al. 57
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Article Title: Maintenance and Regulation in Brain of Neurotransmission, Trophic Factors, and Immune Responses
 

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Carl W. Cotman, Jennifer S. Kahle, Andrew R. Korotzer. Maintenance and Regulation in Brain of Neurotransmission, Trophic Factors, and Immune Responses. Compr Physiol 2011, Supplement 28: Handbook of Physiology, Aging: 345-362. First published in print 1995. doi: 10.1002/cphy.cp110113