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Glutathione restores the mechanism of synaptic plasticity in aged mice to that of the adult.

Robillard JM, Gordon GR, Choi HB, Christie BR, MacVicar BA - PLoS ONE (2011)

Bottom Line: During aging, an increase in oxidative stress leads to decreased levels of GSH in the brain.Concurrently, aging is characterized by calcium dysregulation, thought to underlie impairments in hippocampal NMDAR-dependent long-term potentiation (LTP), a form of synaptic plasticity thought to represent a cellular model for memory.We conclude that aging leads to a reduced redox potential in hippocampal neurons, triggering impairments in LTP.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Brain Research Centre, University of British Columbia, Vancouver, Canada.

ABSTRACT
Glutathione (GSH), the major endogenous antioxidant produced by cells, can modulate the activity of N-methyl-D-aspartate receptors (NMDARs) through its reducing functions. During aging, an increase in oxidative stress leads to decreased levels of GSH in the brain. Concurrently, aging is characterized by calcium dysregulation, thought to underlie impairments in hippocampal NMDAR-dependent long-term potentiation (LTP), a form of synaptic plasticity thought to represent a cellular model for memory. Here we show that orally supplementing aged mice with N-acetylcysteine, a precursor for the formation of glutathione, reverses the L-type calcium channel-dependent LTP seen in aged animals to NMDAR-dependent LTP. In addition, introducing glutathione in the intrapipette solution during whole-cell recordings restores LTP obtained in whole-cell conditions in the aged hippocampus. We conclude that aging leads to a reduced redox potential in hippocampal neurons, triggering impairments in LTP.

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Related in: MedlinePlus

GSH improves NMDAR calcium signals in aged mice.(A) Representative calcium signal traces in control (blue) and during APV (red) or nimodipine (green) from an aged NAC-fed mouse in response to HFS. (B) Summary data of calcium signal integral (area under the curve). Only NMDAR blockade reduces the calcium signal (APV: n = 6, nimodipine: n = 5, P = 0.02). (C) Representative calcium signal traces (same color scheme as a) from an aged control-fed mouse in response to HFS. (D) Summary data of calcium signal integral (area under the curve). Only nimodipine blockade reduces the calcium signal (APV: n = 5, nimodipine: n = 6, P = 0.02).
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pone-0020676-g003: GSH improves NMDAR calcium signals in aged mice.(A) Representative calcium signal traces in control (blue) and during APV (red) or nimodipine (green) from an aged NAC-fed mouse in response to HFS. (B) Summary data of calcium signal integral (area under the curve). Only NMDAR blockade reduces the calcium signal (APV: n = 6, nimodipine: n = 5, P = 0.02). (C) Representative calcium signal traces (same color scheme as a) from an aged control-fed mouse in response to HFS. (D) Summary data of calcium signal integral (area under the curve). Only nimodipine blockade reduces the calcium signal (APV: n = 5, nimodipine: n = 6, P = 0.02).

Mentions: To further test the impact of increasing brain GSH levels on NMDAR function in aged mice, we used two-photon imaging to determine the contribution of NMDARs to hippocampal dendritic calcium signals elicited by bursts of HFS. Consistent with the mechanisms observed in fEPSPs, we found that calcium signals elicited by HFS were depressed by APV only in NAC-fed aged mice (Figure 3, A and B) but not in control-fed aged mice (Figure 3, C and D). These results are consistent with the idea that supplementation with a GSH precursor can restore the NMDAR-dependence of hippocampal LTP by enhancing NMDA calcium influx.


Glutathione restores the mechanism of synaptic plasticity in aged mice to that of the adult.

Robillard JM, Gordon GR, Choi HB, Christie BR, MacVicar BA - PLoS ONE (2011)

GSH improves NMDAR calcium signals in aged mice.(A) Representative calcium signal traces in control (blue) and during APV (red) or nimodipine (green) from an aged NAC-fed mouse in response to HFS. (B) Summary data of calcium signal integral (area under the curve). Only NMDAR blockade reduces the calcium signal (APV: n = 6, nimodipine: n = 5, P = 0.02). (C) Representative calcium signal traces (same color scheme as a) from an aged control-fed mouse in response to HFS. (D) Summary data of calcium signal integral (area under the curve). Only nimodipine blockade reduces the calcium signal (APV: n = 5, nimodipine: n = 6, P = 0.02).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3105108&req=5

pone-0020676-g003: GSH improves NMDAR calcium signals in aged mice.(A) Representative calcium signal traces in control (blue) and during APV (red) or nimodipine (green) from an aged NAC-fed mouse in response to HFS. (B) Summary data of calcium signal integral (area under the curve). Only NMDAR blockade reduces the calcium signal (APV: n = 6, nimodipine: n = 5, P = 0.02). (C) Representative calcium signal traces (same color scheme as a) from an aged control-fed mouse in response to HFS. (D) Summary data of calcium signal integral (area under the curve). Only nimodipine blockade reduces the calcium signal (APV: n = 5, nimodipine: n = 6, P = 0.02).
Mentions: To further test the impact of increasing brain GSH levels on NMDAR function in aged mice, we used two-photon imaging to determine the contribution of NMDARs to hippocampal dendritic calcium signals elicited by bursts of HFS. Consistent with the mechanisms observed in fEPSPs, we found that calcium signals elicited by HFS were depressed by APV only in NAC-fed aged mice (Figure 3, A and B) but not in control-fed aged mice (Figure 3, C and D). These results are consistent with the idea that supplementation with a GSH precursor can restore the NMDAR-dependence of hippocampal LTP by enhancing NMDA calcium influx.

Bottom Line: During aging, an increase in oxidative stress leads to decreased levels of GSH in the brain.Concurrently, aging is characterized by calcium dysregulation, thought to underlie impairments in hippocampal NMDAR-dependent long-term potentiation (LTP), a form of synaptic plasticity thought to represent a cellular model for memory.We conclude that aging leads to a reduced redox potential in hippocampal neurons, triggering impairments in LTP.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Brain Research Centre, University of British Columbia, Vancouver, Canada.

ABSTRACT
Glutathione (GSH), the major endogenous antioxidant produced by cells, can modulate the activity of N-methyl-D-aspartate receptors (NMDARs) through its reducing functions. During aging, an increase in oxidative stress leads to decreased levels of GSH in the brain. Concurrently, aging is characterized by calcium dysregulation, thought to underlie impairments in hippocampal NMDAR-dependent long-term potentiation (LTP), a form of synaptic plasticity thought to represent a cellular model for memory. Here we show that orally supplementing aged mice with N-acetylcysteine, a precursor for the formation of glutathione, reverses the L-type calcium channel-dependent LTP seen in aged animals to NMDAR-dependent LTP. In addition, introducing glutathione in the intrapipette solution during whole-cell recordings restores LTP obtained in whole-cell conditions in the aged hippocampus. We conclude that aging leads to a reduced redox potential in hippocampal neurons, triggering impairments in LTP.

Show MeSH
Related in: MedlinePlus