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Celsr2 regulates NMDA receptors and dendritic homeostasis in dorsal CA1 to enable social memory

Abstract

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.

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Fig. 1: Celsr2 deficiency impairs social memory.
Fig. 2: Celsr2 deficiency results in reduced CA1 pyramidal neuron activity during social tasks.
Fig. 3: Celsr2 deficiency induces the dysfunction of NMDAR and impairment of synaptic plasticity in dCA1.
Fig. 4: Celsr2 deficiency leads to exuberant dendrite formation in vivo.
Fig. 5: Celsr2 knockdown in adulthood recapitulates social memory and spine deficits.
Fig. 6: Rescuing social deficits in Celsr2 KO mice by enhancing NMDAR function or CA1 neuron activity.

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Acknowledgements

We thank Yuying Li for technical assistance with WB experiments.

Funding

This work was supported by National Science and Technology Innovation 2030 Major Project of China (2021ZD0203900). This study was also supported by National Natural Science Foundation of China (82071261, 31671067 and U1801287 to Y.Q.), Key-Area Research and Development Program of Guangdong Province (2018B030340001) to YQ, Guangdong Natural Science Funds for Distinguished Young Scholars (2016A030306001) to YQ, and Guangdong Province Special Support Program (2015TQ01R837) to YQ, National Natural Science Foundation of China (81870869,41030830 to BJ), Guangdong Key Project in “Development of new tools for diagnosis and treatment of Autism” (2018B030335001) to BJ, Research and Development Plan of Key Areas of Guangzhou Science and Technology Bureau (2020070030001) to BJ, and Open Research Funds of State Key Laboratory of Ophthalmology (2020KF08) to BJ.

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BC, KZ, HC, and WN performed mice crossing, behavioral tests, and histological studies. LW and BJ performed the electrophysiological studies. XL performed primary neuron culture experiments. ZS performed molecular assays. BC, JW, and CL carried out in vivo imaging and stereotaxic injection and analyzed data. JD, DW, and CP assisted in the behavioral tests. LZ assisted in the design and analysis of calcium recording assay. YQ, BJ, TY, KS, and LBZ designed and supervised the project. The manuscript was prepared by YQ, TY, BJ, and BC with input from all authors.

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Correspondence to Bin Jiang, Ti-Fei Yuan or Yibo Qu.

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Chen, B., Wang, L., Li, X. et al. Celsr2 regulates NMDA receptors and dendritic homeostasis in dorsal CA1 to enable social memory. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01664-x

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