Memantine prevents acute stress‐induced memory deficits by reversing sex‐dependent pathophysiological glutamatergic alterations in the dorsal hippocampus

Background and Purpose The neural mechanisms underlying effects of acute stress on memory are poorly understood. We demonstrated previously that acute stress produces identical spatial memory deficits in male and female mice but through distinct molecular mechanisms, with females exhibiting up-regulation of N-methyl-D-aspartate (NMDA) receptor subunits in the dorsal hippocampus (dHPC). Here, we tested whether pharmacological manipulation of NMDA receptors prevents stress-induced memory deficits and hippocampal glutamatergic dysfunction in a sex-dependent manner.Experimental Approach Male and female mice were exposed to 2 hours of restraint stress. We performed electrophysiological and molecular analysis of the glutamatergic synapse in the dHPC. We evaluated two non-competitive NMDA receptor antagonists administered pre-stress: MK-801, which blocks synaptic and extrasynaptic NMDA receptors, and memantine, which preferentially blocks extrasynaptic NMDA receptors. We evaluated effects of both drugs on stress-induced spatial memory impairment and the effect of memantine on hippocampal glutamatergic neurotransmission.Key Results Acute stress induces sex- and time-dependent alterations in glutamate-glutamine metabolism, with a striking increase in stressed females. This outcome was associated with female glutamatergic neurotransmission impairment, indicated by reduced miniature EPSC amplitude and AMPA/NMDA ratio at CA3-CA1 synapses. MK-801 and memantine rescued stress-induced spatial memory impairment in male and female mice, respectively. Memantine counteracted stress-induced reduction in AMPA/NMDA ratio in female mice, normalising synaptic strength at CA3-CA1 synapses.Conclusions and Implications Acute stress disrupts hippocampal glutamatergic homeostasis through sex-dependent pathophysiological mechanisms. The study of sex-dependent mechanisms may lead to targeted pharmacological treatments for cognitive deficits in stress-related disorders.