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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Tanimizu T, Kenney JW, Okano E, Kadoma K, Frankland PW, Kida S. Functional connectivity of multiple brain regions required for the consolidation of social recognition memory. J Neurosci. 2017;37:4103–16.
Guo B, Chen J, Chen Q, Ren K, Feng D, Mao H, et al. Anterior cingulate cortex dysfunction underlies social deficits in Shank3 mutant mice. Nat Neurosci. 2019;22:1223–34.
Okuyama T, Kitamura T, Roy DS, Itohara S, Tonegawa S. Ventral CA1 neurons store social memory. Science. 2016;353:1536–41.
Chai AP, Chen XF, Xu XS, Zhang N, Li M, Li JN, et al. A temporal activity of CA1 neurons underlying short-term memory for social recognition altered in PTEN mouse models of autism spectrum disorder. Front Cell Neurosci. 2021;15:699315.
Sellami A, Al Abed AS, Brayda-Bruno L, Etchamendy N, Valerio S, Oule M, et al. Temporal binding function of dorsal CA1 is critical for declarative memory formation. Proc Natl Acad Sci USA 2017;114:10262–7.
Hitti FL, Siegelbaum SA. The hippocampal CA2 region is essential for social memory. Nature. 2014;508:88–92.
Watarai A, Tao K, Wang MY, Okuyama T. Distinct functions of ventral CA1 and dorsal CA2 in social memory. Curr Opin Neurobiol. 2021;68:29–35.
Yang J, Ma Q, Dincheva I, Giza J, Jing D, Marinic T, et al. SorCS2 is required for social memory and trafficking of the NMDA receptor. Mol Psychiatry. 2021;26:927–40.
Tissir F, Goffinet AM. Shaping the nervous system: role of the core planar cell polarity genes. Nat Rev Neurosci. 2013;14:525–35.
Tissir F, Qu Y, Montcouquiol M, Zhou L, Komatsu K, Shi D, et al. Lack of cadherins Celsr2 and Celsr3 impairs ependymal ciliogenesis, leading to fatal hydrocephalus. Nat Neurosci. 2010;13:700–7.
Qu Y, Glasco DM, Zhou L, Sawant A, Ravni A, Fritzsch B, et al. Atypical cadherins Celsr1-3 differentially regulate migration of facial branchiomotor neurons in mice. J Neurosci. 2010;30:9392–401.
Qu Y, Huang Y, Feng J, Alvarez-Bolado G, Grove EA, Yang Y, et al. Genetic evidence that Celsr3 and Celsr2, together with Fzd3, regulate forebrain wiring in a Vangl-independent manner. Proc Natl Acad Sci USA 2014;111:E2996–3004.
Shima Y, Kengaku M, Hirano T, Takeichi M, Uemura T. Regulation of dendritic maintenance and growth by a mammalian 7-pass transmembrane cadherin. Dev Cell. 2004;7:205–16.
Shima Y, Kawaguchi SY, Kosaka K, Nakayama M, Hoshino M, Nabeshima Y, et al. Opposing roles in neurite growth control by two seven-pass transmembrane cadherins. Nat Neurosci. 2007;10:963–9.
Schafer ST, Han J, Pena M, von Bohlen Und Halbach O, Peters J, Gage FH. The Wnt adaptor protein ATP6AP2 regulates multiple stages of adult hippocampal neurogenesis. J Neurosci. 2015;35:4983–98.
Tissir F, De-Backer O, Goffinet AM, Lambert, de Rouvroit C. Developmental expression profiles of Celsr (Flamingo) genes in the mouse. Mech Dev. 2002;112:157–60.
Wen Q, Weng H, Liu T, Yu L, Zhao T, Qin J, et al. Inactivating Celsr2 promotes motor axon fasciculation and regeneration in mouse and human. Brain. 2022;145:670–83.
Takata A, Ionita-Laza I, Gogos Joseph A, Xu B, Karayiorgou M. De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia. Neuron. 2016;89:940–7.
Gulsuner S, Walsh T, Watts AC, Lee MK, Thornton AM, Casadei S, et al. Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell. 2013;154:518–29.
Bacchelli E, Loi E, Cameli C, Moi L, Vega-Benedetti AF, Blois S, et al. Analysis of a Sardinian multiplex family with autism spectrum disorder points to post-synaptic density gene variants and identifies CAPG as a functionally relevant candidate gene. J Clin Med. 2019;8:212.
Al-Mubarak B, Abouelhoda M, Omar A, AlDhalaan H, Aldosari M, Nester M, et al. Whole exome sequencing reveals inherited and de novo variants in autism spectrum disorder: a trio study from Saudi families. Sci Rep. 2017;7:5679.
Vilboux T, Malicdan MC, Roney JC, Cullinane AR, Stephen J, Yildirimli D, et al. CELSR2, encoding a planar cell polarity protein, is a putative gene in Joubert syndrome with cortical heterotopia, microophthalmia, and growth hormone deficiency. Am J Med Genet A. 2017;173:661–6.
Feng G, Mellor RH, Bernstein M, Keller-Peck C, Nguyen QT, Wallace M, et al. Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron. 2000;28:41–51.
Madisen L, Zwingman TA, Sunkin SM, Oh SW, Zariwala HA, Gu H, et al. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci. 2010;13:133–40.
Lagace DC, Whitman MC, Noonan MA, Ables JL, DeCarolis NA, Arguello AA, et al. Dynamic contribution of nestin-expressing stem cells to adult neurogenesis. J Neurosci. 2007;27:12623–9.
Tripodi M, Evers JF, Mauss A, Bate M, Landgraf M. Structural homeostasis: compensatory adjustments of dendritic arbor geometry in response to variations of synaptic input. PLoS Biol. 2008;6:e260.
Tavosanis G. Dendritic structural plasticity. Dev Neurobiol. 2012;72:73–86.
Lüthi A, Schwyzer L, Mateos JM, Gähwiler BH, McKinney RA. NMDA receptor activation limits the number of synaptic connections during hippocampal development. Nat Neurosci. 2001;4:1102–7.
Liu XD, Ai PH, Zhu XN, Pan YB, Halford MM, Henkemeyer M, et al. Hippocampal Lnx1-NMDAR multiprotein complex mediates initial social memory. Mol Psychiatry. 2021;26:3956–69.
Zoicas I, Kornhuber J. The role of the N-Methyl-D-Aspartate receptors in social behavior in rodents. Int J Mol Sci. 2019;20:5599.
Duffney LJ, Zhong P, Wei J, Matas E, Cheng J, Qin L, et al. Autism-like deficits in Shank3-deficient mice are rescued by targeting actin regulators. Cell Rep. 2015;11:1400–13.
Guo D, Peng Y, Wang L, Sun X, Wang X, Liang C, et al. Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function. Mol Psychiatry. 2021;26:1505–19.
Gao FB, Kohwi M, Brenman JE, Jan LY, Jan YN. Control of dendritic field formation in Drosophila: the roles of flamingo and competition between homologous neurons. Neuron. 2000;28:91–101.
Kremer MC, Christiansen F, Leiss F, Paehler M, Knapek S, Andlauer TF, et al. Structural long-term changes at mushroom body input synapses. Curr Biol. 2010;20:1938–44.
Cline H, Haas K. The regulation of dendritic arbor development and plasticity by glutamatergic synaptic input: a review of the synaptotrophic hypothesis. J Physiol. 2008;586:1509–17.
Lee LJ, Lo FS, Erzurumlu RS. NMDA receptor-dependent regulation of axonal and dendritic branching. J Neurosci. 2005;25:2304–11.
Singh AP, VijayRaghavan K, Rodrigues V. Dendritic refinement of an identified neuron in the Drosophila CNS is regulated by neuronal activity and Wnt signaling. Development. 2010;137:1351–60.
Zou DJ, Cline HT. Postsynaptic calcium/calmodulin-dependent protein kinase II is required to limit elaboration of presynaptic and postsynaptic neuronal arbors. J Neurosci. 1999;19:8909–18.
Rocha M, Sur M. Rapid acquisition of dendritic spines by visual thalamic neurons after blockade of N-methyl-D-aspartate receptors. Proc Natl Acad Sci USA 1995;92:8026–30.
Goffinet AM, Tissir F. Seven pass Cadherins CELSR1-3. Semin Cell Dev Biol. 2017;69:102–10.
Nagaoka T, Ohashi R, Inutsuka A, Sakai S, Fujisawa N, Yokoyama M, et al. The Wnt/planar cell polarity pathway component Vangl2 induces synapse formation through direct control of N-cadherin. Cell Rep. 2014;6:916–27.
Nagaoka T, Kishi M. The planar cell polarity protein Vangl2 is involved in postsynaptic compartmentalization. Neurosci Lett. 2016;612:251–5.
Okerlund ND, Stanley RE, Cheyette BN. The planar cell polarity transmembrane protein Vangl2 promotes dendrite, spine and glutamatergic synapse formation in the mammalian forebrain. Mol Neuropsychiatry. 2016;2:107–14.
Dos-Santos Carvalho S, Moreau MM, Hien YE, Garcia M, Aubailly N, Henderson DJ, et al. Vangl2 acts at the interface between actin and N-cadherin to modulate mammalian neuronal outgrowth. Elife. 2020;9:e51822.
Hida Y, Fukaya M, Hagiwara A, Deguchi-Tawarada M, Yoshioka T, Kitajima I, et al. Prickle2 is localized in the postsynaptic density and interacts with PSD-95 and NMDA receptors in the brain. J Biochem. 2011;149:693–700.
Sowers LP, Loo L, Wu Y, Campbell E, Ulrich JD, Wu S, et al. Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction. Mol Psychiatry. 2013;18:1077–89.
Thakar S, Wang L, Yu T, Ye M, Onishi K, Scott J, et al. Evidence for opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation. Proc Natl Acad Sci USA 2017;114:E610–E8.
Feng B, Freitas AE, Gorodetski L, Wang J, Tian R, Lee YR, et al. Planar cell polarity signaling components are a direct target of β-amyloid-associated degeneration of glutamatergic synapses. Sci Adv. 2021;7:eabh2307.
We thank Yuying Li for technical assistance with WB experiments.
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.
The authors declare no competing interests.
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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