Social memory engram formation impairment in neuroligin-3 R451C knock-in mice is caused by disrupted prefrontal NMDA receptor-dependent potentiation.

Abstract

Autism spectrum disorders (ASDs) are characterized by profound social cognitive deficits, including impairments in social memory-the ability to recognize and remember familiar conspecifics. However, the mechanisms underlying these deficits remain poorly understood. Here, we identify a distinct population of medial prefrontal cortical neurons that encode individual conspecifics and form social memory engram cells (SMECs) through N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP). Using the Neuroligin 3 R451C knock-in mouse model of autism, we demonstrate that disrupted NMDAR-dependent LTP impairs the formation of SMECs, leading to social memory deficits. Notably, these deficits are rescued by a well-tolerated, once-weekly "pulsed" administration of D-cycloserine, a partial NMDAR agonist. Our findings underscore the pivotal role of NMDAR-dependent synaptic plasticity in social memory encoding and position NMDAR-targeted therapies as a compelling avenue for addressing social cognitive deficits in ASDs.