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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月30日

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  • Zhiyuan Li,
  • Qun Yang,
  • Huiyi Li,
  • Jiali Ge,
  • Hangtian Yan,
  • Jiahui Li,
  • Yuzhen Fu,
  • Kexian Yan,
  • Sien Li,
  • Jialin Chen,
  • Wenjie Dou,
  • Junyu Xu,
  • Jianhong Luo,
  • Baoming Li,
  • Wei Cao

摘要

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.