NMDA Receptor Function During Senescence: Implication on Cognitive Performance

Abstract

N-methyl-D-aspartate (NMDA) receptors, a family of L-glutamate receptors, play an important role in learning and memory, and are critical for spatial memory. These receptors are tetrameric ion channels composed of a family of related subunits. One of the hallmarks of the aging human population is a decline in cognitive function; studies in the past couple of years have demonstrated deterioration in NMDA receptor subunit expression and function with advancing age. However, a direct relationship between impaired memory function and a decline in NMDA receptors is still ambiguous. Recent studies indicate a link between an age-associated NMDA receptor hypofunction and memory impairment and provide evidence that age-associated enhanced oxidative stress might be contributing to the alterations associated with senescence. However, clear evidence is still deficient in demonstrating the underlying mechanisms and a relationship between age-associated impaired cognitive faculties and NMDA receptor hypofunction. The current review intends to present an overview of the research findings regarding changes in expression of various NMDA receptor subunits and deficits in NMDA receptor function during senescence and its implication in age-associated impaired hippocampal-dependent memory function.

Alteration in NMDA Receptor Mediated Glutamatergic Neurotransmission in the Hippocampus During Senescence

“…NMDA receptors are hetero-tetrameric protein complexes composed of two classes of related subunits from seven homologous genes, GluN1, GluN2A-GluN2D, and GluN3A-GluN3B [29–36]. The majority of NMDA receptors are assemblies of two GluN1 subunits, the ubiquitously expressed and obligatory subunit, and two GluN2A-D subunits, a modulatory subunit.…”

Asc‐1 transporter activation: an alternative to rescue age‐related alterations in functional plasticity at rat hippocampal CA3/CA1 synapses

“…In aged rats, we reveal a similar and even higher potentiation effect of d ‐Ile indicating that the selective modulation of Asc‐1 transporters on NMDA‐R activation is preserved throughout the lifespan. Although this selective Asc‐1 activation does not fully reverse the well‐documented age‐related decrease in NMDA‐R‐mediated synaptic potentials (see (Billard ; Kumar ) for reviews), it appears effective enough to restore a potent NMDA‐R‐mediated functional plasticity at CA3/CA1 synapses of the ageing hippocampus. This result thus provides further evidence that the specific targeting of Asc‐1 transporters may be useful in the search of an alternative strategy aimed at reducing synaptic deficits linked to age‐related memory decline.…”

Temporal and Spatial Differential Expression of Glutamate Receptor Genes in the Brain of Down Syndrome

“…NMDA receptors are present in high density within the hippocampus and the cerebral cortex performing fundamental physiological and pathophysiological functions in the central nervous system [38], among which learning, memory, brain plasticity, and recovery of injuries stand out. In these brain structures, differential expression of these receptors is evidenced, where a change in their dynamics could contribute to changes in cognitive and synaptic function [39]. When treated in conjunction with AMPA, they are attributed an important role in plasticity and synaptic transmission in many postsynaptic membranes [35,40], with the latter receptors participating in protein-protein interactions with scaffolding proteins, such as PICK1 and GRIP1, and the TARP accessory proteins that help in AMPA receptor traffic and present additional targets for regulation [37].…”