Social interaction and communication are evolutionary conserved behaviours that are developed in mammals to establish partner cognition. Deficit in sociability has been represented in human patients and animal models of neurodevelopmental disorders, which are connected with genetic variants of synaptic glutamate receptors and associated PDZ-binding proteins. However, it remains elusive how these key proteins are specialized in the cellular level for the initial social behaviour during postnatal developmental stage. Here we identify a hippocampal CA3 specifically expressed PDZ scaffold protein Lnx1 required for initial social behaviour. Through gene targeting we find that Lnx1 deficiency led to a hippocampal subregional disorder in neuronal activity and social memory impairments for partner discrimination observed in juvenile mice which also show cognitive defects in adult stage. We further demonstrate that Lnx1 deletion causes NMDA receptor (NMDAR) hypofunction and this is attributable to decreased GluN2B expression in PSD compartment and disruption of the Lnx1–NMDAR–EphB2 complex. Specific restoration of Lnx1 or EphB2 protein in the CA3 area of Lnx1^−/− mice rescues the defective synaptic function and social memory. These findings thus reveal crucial roles of postsynaptic NMDAR multiprotein complex that regulates the formation of initial social memory during the adolescent period.

社交互动和交流是哺乳动物进化的保守行为，用于建立伙伴认知。社交能力缺陷已在神经发育障碍的人类患者和动物模型中表现出来，这与突触谷氨酸受体和相关 PDZ 结合蛋白的遗传变异有关。然而，这些关键蛋白如何在细胞水平上专门用于出生后发育阶段的初始社会行为，仍然是个谜。在这里，我们确定了初始社会行为所需的海马 CA3 特异性表达的 PDZ 支架蛋白 Lnx1。通过基因打靶，我们发现 Lnx1 缺陷导致神经元活动的海马亚区域紊乱和在幼年小鼠中观察到的伴侣歧视的社会记忆障碍，这在成年阶段也表现出认知缺陷。我们进一步证明 Lnx1 缺失导致 NMDA 受体 (NMDAR) 功能减退，这归因于 PSD 区室中 GluN2B 表达降低和 Lnx1–NMDAR–EphB2 复合物的破坏。CA3 区 Lnx1 或 EphB2 蛋白的特异性修复Lnx1 ^−/−小鼠挽救了有缺陷的突触功能和社会记忆。因此，这些发现揭示了突触后 NMDAR 多蛋白复合物的关键作用，该复合物在青春期调节初始社会记忆的形成。