Consequences of NMDA Receptor Disruption for Prefrontal Cortical Neurophysiology

Cognitive deficits, indicative of prefrontal cortical disruption, are observed in several neurodevelopmental disorders. Converging evidence suggests these cognitive symptoms arise from abnormalities in N-methyl-D-aspartate (NMDA) receptor function. Indeed, deficits in working memory are observed in transgenic mice with reduced expression of the obligate GluN1 subunit of the NMDA receptor. Here, I examine the prefrontal cortex of GluN1 knockdown mice with a tripartite approach: (1) measuring basic electrophysiological properties, (2) probing the integrity of synaptic and extrasynaptic NMDA receptor responses, and (3) evoking network activity. Many aspects of cellular electrophysiology show surprisingly subtle deficits in the face of lifelong NMDA receptor knockdown, including synaptic currents themselves. Yet, responses to extrasynaptic NMDA stimulation are clearly disrupted, and electricallyâ evoked network activity is absent in GluN1 knockdown mice. As such network activity is thought to be essential for working memory, its disruption in GluN1 knockdown mice would contribute to their observed cognitive deficits.M.Sc