Social recognition and memory are critical for survival. The hippocampus serves as a central neural substrate underlying the dynamic coding and transmission of social information. Yet the molecular mechanisms regulating social memory integrity in hippocampus remain unelucidated. Here we report unexpected roles of Celsr2, an atypical cadherin, in regulating hippocampal synaptic plasticity and social memory in mice. Celsr2-deficient mice exhibited defective social memory, with rather intact levels of sociability. In vivo fiber photometry recordings disclosed decreased neural activity of dorsal CA1 pyramidal neuron in Celsr2 mutants performing social memory task. Celsr2 deficiency led to selective impairment in NMDAR but not AMPAR-mediated synaptic transmission, and to neuronal hypoactivity in dorsal CA1. Those activity changes were accompanied with exuberant apical dendrites and immaturity of spines of CA1 pyramidal neurons. Strikingly, knockdown of Celsr2 in adult hippocampus recapitulated the behavioral and cellular changes observed in knockout mice. Restoring NMDAR transmission or CA1 neuronal activities rescued social memory deficits. Collectively, these results show a critical role of Celsr2 in orchestrating dorsal hippocampal NMDAR function, dendritic and spine homeostasis, and social memory in adulthood.

社会认可和记忆对于生存至关重要。海马体是社会信息动态编码和传递的中枢神经基质。然而，海马体中调节社会记忆完整性的分子机制仍未阐明。在这里，我们报告了 Celsr2（一种非典型钙粘蛋白）在调节小鼠海马突触可塑性和社会记忆方面的意外作用。Celsr2缺陷小鼠表现出有缺陷的社会记忆，具有相当完整的社交能力。体内纤维光度记录显示在执行社会记忆任务的Celsr2突变体中背侧 CA1 锥体神经元的神经活动降低。Celsr2缺乏导致选择性损伤 NMDAR 但不是 AMPAR 介导的突触传递，并导致背部 CA1 的神经元活动减退。这些活动的变化伴随着CA1锥体神经元顶端树突的旺盛和棘的不成熟。引人注目的是，成年海马中Celsr2的敲除重现了在敲除小鼠中观察到的行为和细胞变化。恢复 NMDAR 传输或 CA1 神经元活动可以挽救社会记忆缺陷。总的来说，这些结果表明 Celsr2 在协调海马背侧 NMDAR 功能、树突和脊柱稳态以及成年期的社会记忆方面发挥着关键作用。