Abstract
The molecular processes underlying the ageing-related decline in cognitive performance and memory observed in humans are poorly understood. Studies in rodents have shown that N-methyl-D-aspartate receptors (NMDARs) containing GluN2B subunits can enhance the ability of synapses to undergo long term potentiation. In ageing rodents, the contribution of GluN2B to synaptic function is reduced compared to younger animals and the decline in GluN2B subunit expression is correlated with impaired memory functions. However, the contribution of GluN2B containing receptors to synaptic transmission in cortical synapses has not been previously studied. We investigated the synaptic contribution of GluN2A and GluN2B containing NMDARs in adult human neurons using fresh non-pathological temporal cortical tissue resected during neurosurgical procedures. The tissue we obtained fulfilled quality criteria by the absence of inflammation markers and proteomic degradation. We show an age-dependent decline in the NMDA/AMPA receptor ratio in adult human temporal cortical synapses. We demonstrate that GluN2B containing NMDA receptors contribute to synaptic responses in the adult human brain with a reduced contribution in older individuals. With previous evidence demonstrating the critical role of synaptic GluN2B in regulating synaptic strength and memory storage in mice, this progressive reduction of GluN2B in the human brain during aging may underlie a molecular mechanism in the age-related decline in cognitive abilities and memory observed in humans.