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.
Highlights
The tripeptide glutathione (GSH) is the major endogenous antioxidant produced by cells and is critical for the maintenance of the redox potential in the brain
The data presented here demonstrate that feeding aged mice with the GSH precursor NAC partially restores brain GSH levels and reverses the mechanisms underlying hippocampal long-term potentiation (LTP) in area CA1 from L-type calcium channel dependence to N-methyl-D-apartate glutamate receptors (NMDARs) dependence
This switch is associated with improved NMDAR-mediated calcium signals in aged mice in response to a HFS pattern used to evoke LTP
Summary
The tripeptide glutathione (GSH) is the major endogenous antioxidant produced by cells and is critical for the maintenance of the redox potential in the brain. The concentrations of GSH, a potent reducing agent, decrease in the brain [4], a manifestation of the increase in oxidative stress that accompanies normal aging [5]. This increase is thought to be caused by an imbalance between the production of reactive oxygen species (ROS) and the cellular mechanisms responsible for the scavenging of ROS. Age-related changes in the contributions of various sources to intracellular calcium levels leads to impairments in calcium-dependent signaling processes such as synaptic plasticity (for a review, see [8]). NMDARs are the main sources of calcium influx for LTP induction, and NMDAR-dependent LTP induction is impaired when weaker stimulation protocols are used in aged animals [9]
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