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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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LTP is L-type calcium channel-dependent in aged control-fed mice but NMDAR-dependent in aged NAC-fed mice.(A and B) fEPSP slope in aged NAC-fed mice in control (blue •, n = 7) and with APV (red ▾, n = 6) or with nimodipine(green ▾, n = 9) in response to HFS. Averaged fEPSP traces inset. (C) Summary data: in NAC–fed mice LTP was blocked by APV (P<0.001) but not by nimodipine (P = 0.75). (D and E) fEPSP slope in aged control-fed mice in control conditions (blue •, n = 8) and with APV (red ▾, n = 5) or with nimodipine (green ▾, n = 7) in response to HFS. Averaged fEPSP traces inset. (F) Summary data: LTP in aged, control-fed mice was blocked by nimodipine (P = 0.002) but not by APV (P = 0.24). Scale bars: 10 ms, 0.4 mV. All data are expressed as mean ± s.e.m.
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pone-0020676-g002: LTP is L-type calcium channel-dependent in aged control-fed mice but NMDAR-dependent in aged NAC-fed mice.(A and B) fEPSP slope in aged NAC-fed mice in control (blue •, n = 7) and with APV (red ▾, n = 6) or with nimodipine(green ▾, n = 9) in response to HFS. Averaged fEPSP traces inset. (C) Summary data: in NAC–fed mice LTP was blocked by APV (P<0.001) but not by nimodipine (P = 0.75). (D and E) fEPSP slope in aged control-fed mice in control conditions (blue •, n = 8) and with APV (red ▾, n = 5) or with nimodipine (green ▾, n = 7) in response to HFS. Averaged fEPSP traces inset. (F) Summary data: LTP in aged, control-fed mice was blocked by nimodipine (P = 0.002) but not by APV (P = 0.24). Scale bars: 10 ms, 0.4 mV. All data are expressed as mean ± s.e.m.

Mentions: Redox potential impacts both L-type calcium channels and NMDARs [11], [12]. The activity of NMDARs in particular have been shown to be modulated by the redox state in the environment [12], [13]. This modulation raises the interesting possibility that changing brain GSH levels by supplying a precursor in the diet can modulate synaptic plasticity in the hippocampus. Therefore we repeated our LTP experiments in both NAC-fed aged mice and control-fed aged mice to assess the mechanisms of LTP in mice with altered GSH levels. Remarkably, in the NAC-fed aged mice, LTP was restored back to NMDAR-dependence observed in adult mice, as LTP was completely blocked by APV (control: 159±2%, APV: 102±6%; Figure 2, A and C) but not by nimodipine (control: 159±2%, nimodipine: 155±8%; Figure 2, B and C). In contrast, control-fed aged mice retained their L-type calcium channel-dependence because LTP in these mice was not significantly blocked by APV (control: 157±8%, APV: 139±13%; Figure 2, D and F) but was decreased by nimodipine (control: 157±8%, nimodipine: 118±7%; Figure 2, E and F). These results demonstrate that LTP in aged control-fed mice is mediated by the same mechanisms observed in aged mice and that oral NAC supplementation in aged mice increases brain GSH levels and restores the NMDAR dependency of LTP seen in adult animals.


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)

LTP is L-type calcium channel-dependent in aged control-fed mice but NMDAR-dependent in aged NAC-fed mice.(A and B) fEPSP slope in aged NAC-fed mice in control (blue •, n = 7) and with APV (red ▾, n = 6) or with nimodipine(green ▾, n = 9) in response to HFS. Averaged fEPSP traces inset. (C) Summary data: in NAC–fed mice LTP was blocked by APV (P<0.001) but not by nimodipine (P = 0.75). (D and E) fEPSP slope in aged control-fed mice in control conditions (blue •, n = 8) and with APV (red ▾, n = 5) or with nimodipine (green ▾, n = 7) in response to HFS. Averaged fEPSP traces inset. (F) Summary data: LTP in aged, control-fed mice was blocked by nimodipine (P = 0.002) but not by APV (P = 0.24). Scale bars: 10 ms, 0.4 mV. All data are expressed as mean ± s.e.m.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3105108&req=5

pone-0020676-g002: LTP is L-type calcium channel-dependent in aged control-fed mice but NMDAR-dependent in aged NAC-fed mice.(A and B) fEPSP slope in aged NAC-fed mice in control (blue •, n = 7) and with APV (red ▾, n = 6) or with nimodipine(green ▾, n = 9) in response to HFS. Averaged fEPSP traces inset. (C) Summary data: in NAC–fed mice LTP was blocked by APV (P<0.001) but not by nimodipine (P = 0.75). (D and E) fEPSP slope in aged control-fed mice in control conditions (blue •, n = 8) and with APV (red ▾, n = 5) or with nimodipine (green ▾, n = 7) in response to HFS. Averaged fEPSP traces inset. (F) Summary data: LTP in aged, control-fed mice was blocked by nimodipine (P = 0.002) but not by APV (P = 0.24). Scale bars: 10 ms, 0.4 mV. All data are expressed as mean ± s.e.m.
Mentions: Redox potential impacts both L-type calcium channels and NMDARs [11], [12]. The activity of NMDARs in particular have been shown to be modulated by the redox state in the environment [12], [13]. This modulation raises the interesting possibility that changing brain GSH levels by supplying a precursor in the diet can modulate synaptic plasticity in the hippocampus. Therefore we repeated our LTP experiments in both NAC-fed aged mice and control-fed aged mice to assess the mechanisms of LTP in mice with altered GSH levels. Remarkably, in the NAC-fed aged mice, LTP was restored back to NMDAR-dependence observed in adult mice, as LTP was completely blocked by APV (control: 159±2%, APV: 102±6%; Figure 2, A and C) but not by nimodipine (control: 159±2%, nimodipine: 155±8%; Figure 2, B and C). In contrast, control-fed aged mice retained their L-type calcium channel-dependence because LTP in these mice was not significantly blocked by APV (control: 157±8%, APV: 139±13%; Figure 2, D and F) but was decreased by nimodipine (control: 157±8%, nimodipine: 118±7%; Figure 2, E and F). These results demonstrate that LTP in aged control-fed mice is mediated by the same mechanisms observed in aged mice and that oral NAC supplementation in aged mice increases brain GSH levels and restores the NMDAR dependency of LTP seen in adult animals.

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