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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 NMDAR-dependent in adult mice but L-type calcium channel-dependent in aged mice.(A and B) CA1 fEPSP slope in adult mice in control conditions (blue •, n = 14) and with APV (50 µM) (red ▾, n = 11) or nimodipine (10 µM) (green ▾, n = 8) in response to HFS applied at t = 0. Inset, averaged fEPSP traces. (C) Summary data:in adult, LTP is blocked by APV (P = 0.01) but not by nimodipine (P = 0.81). (D and E) fEPSP slope in aged mice in control (blue •, n = 7) and with APV (red ▾, n = 8) or with nimodipine (green ▾, n = 6) in response to HFS. Inset, averaged fEPSP traces. (F) Summary data: in contrast to adult, LTP in aged mice is blocked by nimodipine (P = 0.01) but not by APV (P = 0.48). Scale bars: 10 ms, 0.4 mV. All data are expressed as mean ± s.e.m.
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pone-0020676-g001: LTP is NMDAR-dependent in adult mice but L-type calcium channel-dependent in aged mice.(A and B) CA1 fEPSP slope in adult mice in control conditions (blue •, n = 14) and with APV (50 µM) (red ▾, n = 11) or nimodipine (10 µM) (green ▾, n = 8) in response to HFS applied at t = 0. Inset, averaged fEPSP traces. (C) Summary data:in adult, LTP is blocked by APV (P = 0.01) but not by nimodipine (P = 0.81). (D and E) fEPSP slope in aged mice in control (blue •, n = 7) and with APV (red ▾, n = 8) or with nimodipine (green ▾, n = 6) in response to HFS. Inset, averaged fEPSP traces. (F) Summary data: in contrast to adult, LTP in aged mice is blocked by nimodipine (P = 0.01) but not by APV (P = 0.48). Scale bars: 10 ms, 0.4 mV. All data are expressed as mean ± s.e.m.

Mentions: We initially established the mechanisms underlying LTP in both adult and aged mice. Field excitatory postsynaptic potentials (fEPSPs) were recorded in area CA1 of hippocampal slices from adult (2–4 months old) and aged (14–18 months old) mice. A high-frequency stimulation (HFS) protocol was used to elicit LTP. In the adult hippocampus LTP was blocked by the NMDAR antagonist (2R-amino-5-phosphonovaleric acid (APV) (50 µM) (control: 153±12%, APV: 112±8%; Figure 1, A and C) but not by the L-type calcium channel antagonist nimodipine (NIMO) (10 µM) (control: 153±12%, nimodipine: 149±10%; Figure 1, B and C). In contrast, LTP in aged mice was not significantly blocked by APV (control: 158±9%, APV: 146±13%; Figure 1, D and F) but was significantly decreased by nimodipine (control: 158±9%, nimodipine: 126±6%; Figure 1, E and F). Therefore, these findings confirm in a naturally aged mouse model that LTP in adults is NMDAR-dependent whereas LTP in aged mice is L-type calcium channel-dependent.


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 NMDAR-dependent in adult mice but L-type calcium channel-dependent in aged mice.(A and B) CA1 fEPSP slope in adult mice in control conditions (blue •, n = 14) and with APV (50 µM) (red ▾, n = 11) or nimodipine (10 µM) (green ▾, n = 8) in response to HFS applied at t = 0. Inset, averaged fEPSP traces. (C) Summary data:in adult, LTP is blocked by APV (P = 0.01) but not by nimodipine (P = 0.81). (D and E) fEPSP slope in aged mice in control (blue •, n = 7) and with APV (red ▾, n = 8) or with nimodipine (green ▾, n = 6) in response to HFS. Inset, averaged fEPSP traces. (F) Summary data: in contrast to adult, LTP in aged mice is blocked by nimodipine (P = 0.01) but not by APV (P = 0.48). 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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pone-0020676-g001: LTP is NMDAR-dependent in adult mice but L-type calcium channel-dependent in aged mice.(A and B) CA1 fEPSP slope in adult mice in control conditions (blue •, n = 14) and with APV (50 µM) (red ▾, n = 11) or nimodipine (10 µM) (green ▾, n = 8) in response to HFS applied at t = 0. Inset, averaged fEPSP traces. (C) Summary data:in adult, LTP is blocked by APV (P = 0.01) but not by nimodipine (P = 0.81). (D and E) fEPSP slope in aged mice in control (blue •, n = 7) and with APV (red ▾, n = 8) or with nimodipine (green ▾, n = 6) in response to HFS. Inset, averaged fEPSP traces. (F) Summary data: in contrast to adult, LTP in aged mice is blocked by nimodipine (P = 0.01) but not by APV (P = 0.48). Scale bars: 10 ms, 0.4 mV. All data are expressed as mean ± s.e.m.
Mentions: We initially established the mechanisms underlying LTP in both adult and aged mice. Field excitatory postsynaptic potentials (fEPSPs) were recorded in area CA1 of hippocampal slices from adult (2–4 months old) and aged (14–18 months old) mice. A high-frequency stimulation (HFS) protocol was used to elicit LTP. In the adult hippocampus LTP was blocked by the NMDAR antagonist (2R-amino-5-phosphonovaleric acid (APV) (50 µM) (control: 153±12%, APV: 112±8%; Figure 1, A and C) but not by the L-type calcium channel antagonist nimodipine (NIMO) (10 µM) (control: 153±12%, nimodipine: 149±10%; Figure 1, B and C). In contrast, LTP in aged mice was not significantly blocked by APV (control: 158±9%, APV: 146±13%; Figure 1, D and F) but was significantly decreased by nimodipine (control: 158±9%, nimodipine: 126±6%; Figure 1, E and F). Therefore, these findings confirm in a naturally aged mouse model that LTP in adults is NMDAR-dependent whereas LTP in aged mice is L-type calcium channel-dependent.

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