Abstract
We examined the contribution of N-methyl-D-aspartate receptor (NMDAR) subunits in the redox-mediated decline in NMDAR function during aging. GluN2A and GluN2B selective antagonists decreased peak NMDAR currents to a similar extent in young and aged animals, indicating that a shift in diheteromeric GluN2 subunits does not underlie the age-related decrease in the NMDAR synaptic function. Application of dithiothreitol (DTT) in aged animals, increased peak NMDAR synaptic currents, prolonged the decay time, and increased the sensitivity of the synaptic response to the GluN2B antagonist, ifenprodil, indicating that DTT increased the contribution of GluN2B subunits to the synaptic response. The DTT-mediated increase in NMDAR function was inhibited by partial blockade of NMDARs, and this inhibition was rescued by increasing Ca2+ concentration in the recording medium. The results indicate that DTT-mediated potentiation requires Ca2+ influx through NMDAR activity. Finally, redox regulation of NMDAR function depends on the activity of Ca2+/calmodulin-dependent protein kinase II (CaMKII). The results indicate that activity-dependent NMDAR synaptic plasticity is suppressed by redox-mediated inhibition of CaMKII activation during aging. The redox regulation of NMDARs represents a suppression of a metaplasticity mechanism, which can disrupt synaptic plasticity and cognition associated with neurological or psychiatric diseases, and aging.
Highlights
The function of N-methyl-D-aspartate receptors (NMDARs) have a profound influence on synaptic plasticity, cognition, psychiatric diseases, and the connectivity of neural networks [1, 2]
Whole-cell patch-clamp recordings of synaptically evoked NMDAR-mediated excitatory postsynaptic currents (EPSCs) were obtained from CA1 pyramidal cells of hippocampal slices obtained from young (11/4 cells/animals) and aged (9/4 cells/animals) animals
Redox-mediated NMDAR hypofunction is linked to cognitive deficits for a range of illnesses including Alzheimer’s disease, depression, and schizophrenia [4, 41, 42]
Summary
The function of N-methyl-D-aspartate receptors (NMDARs) have a profound influence on synaptic plasticity, cognition, psychiatric diseases, and the connectivity of neural networks [1, 2]. The results point to a redox sensitive mechanism in mediating the wellcharacterized decrease in the CA3-CA1 NMDAR synaptic response of older-memory impaired animals, and suggests that redox regulation of NMDARs influences synaptic plasticity during aging [15,16,17,18]. Due to the redox sensitive cysteine residues of GluN2A, a shift in the ratio of GluN2A/GluN2B could render older synapses more susceptible to redox regulation In this case, DTT should increase the GluN2A contribution to the synaptic response. The current study, recorded synaptically evoked excitatory postsynaptic currents (EPSCs) from CA1 hippocampal pyramidal neurons and field excitatory postsynaptic potentials (fEPSPs) from CA3-CA1 synapses, and examined the contribution of GluN2A and GluN2B subunits to the decline in NMDAR synaptic function during aging, and the DTT-induced enhancement of NMDAR-mediated synaptic transmission. The results suggest that increased oxidative stress during aging suppresses NMDAR activity-dependent plasticity
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