自闭症谱系障碍被认为是由突触功能缺陷导致特定神经环路功能紊乱引起。神经连接蛋白（NL）属于细胞粘附分子，是突触前Neurexin的突触后配体，与突触发生和传递密切相关。NL有四种主要亚型，NL3的R451C点突变与自闭症相关，该点突变的基因敲入（KI）小鼠也表现出自闭症样行为，包括社交趋新缺陷。最近我们在Neuron上报道该KI小鼠前额叶皮层（mPFC）的PV中间神经元和场电位gamma振荡功能障碍是社交缺陷的原因。我们前期研究还发现该KI小鼠mPFC中锥体神经元的NMDA受体功能下降、部分激动剂D-环丝氨酸（DCS）可拯救小鼠社交缺陷，但分子细胞机制尚不清楚。本项目拟明确NMDA受体在该KI小鼠分子病理学中的关键作用，在神经元亚型和局部环路功能水平阐明其分子细胞机制，并系统研究DCS改善社交缺陷的突触和细胞基础，这将有助于深入认识自闭症社交缺陷的发病机制并提出新的治疗靶点。

Autism spectrum disorders are deemed to result from dysfunction of specific neural circuits caused by deficits in synaptic transmission. Neuroligins (NLs) are cell-adhesion molecules that act as postsynaptic ligands for presynaptic neurexins, contributing to synaptogenesis and synaptic transmission. NLs are expressed as four principal isoforms and a mutation of NL3, R451C, is associated with autism. Knock-in (KI) mice with the mutation exhibit autistic behavioral abnormalities, including deficits in social novelty behavior. Our article recently published on Neuron reports that the abnormalities of PV interneurons and gamma oscillation in the medial prefrontal cortex (mPFC) are the cause of behavioral defects of KI mice. Our previous study also found that NMDARs function of pyramidal neurons in the mPFC was decreased and the D-cycloserine (DCS), a partial agonist of NMDARs, could rescue social behavioral deficits in KI mice. However, its cellular and molecular mechanisms remain to be further elucidated. In this research, we aim to identify the key role of NMDARs in the molecular pathology of KI mice, to elucidate its molecular and cellular mechanisms in different subtypes of neurons of local neural circuits, and to systematically study the synaptic and cellular basis of DCS for improving social defects, which will help us understand the pathogenesis of social deficits in autism and propose new therapeutic targets.