Autism-Risk Gene necab2 Regulates Psychomotor and Social Behavior as a Neuronal Modulator of mGluR1 Signaling

文献类型： 外文期刊

第一作者： Chen, Zexu

作者： Chen, Zexu;Long, Han;Guo, Jianhua;Wang, Yiran;He, Kezhe;Li, Xiong;Pi, Yan;Chen, Zexu;Long, Han;Guo, Jianhua;Wang, Yiran;He, Kezhe;Li, Xiong;Pi, Yan;Chen, Zexu;Chen, Zexu;Chen, Zexu;Wang, Yiran;Tao, Chenchen;Wang, Yiran;Li, Xiong;Guo, Su;Tao, Chenchen;Jiang, Keji

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关键词： autism spectrum disorders; calcium-binding protein; social behavior; metabotropic glutamate receptor 1; cerebellum

期刊名称：FRONTIERS IN MOLECULAR NEUROSCIENCE （ 影响因子：6.261； 五年影响因子：6.187 ）

ISSN： 1662-5099

年卷期： 2022 年 15 卷

页码：

收录情况： SCI

摘要： Background: De novo deletion of the neuronal calcium-binding protein 2 (NECAB2) locus is associated with idiopathic autism spectrum disorders (ASDs). The in vivo function of NECAB2 in the brain remains largely elusive. Methods: We investigated the morphological and behavioral profiles of both necab2 knock-out and overexpression zebrafish models. The expression pattern and molecular role of necab2 were probed through a combination of in vitro and in vivo assays. Results: We show that Necab2 is a neuronal specific, cytoplasmic, and membrane-associated protein, abundantly expressed in the telencephalon, habenula, and cerebellum. Necab2 is distributed pen-synaptically in subsets of glutamatergic and GABAergic neurons. CRISPR/Cas9-generated necab2 knock-out zebrafish display normal morphology but exhibit a decrease in locomotor activity and thigmotaxis with impaired social interaction only in males. Conversely, necab2 overexpression yields behavioral phenotypes opposite to the loss-of-function. Proteomic profiling uncovers a role of Necab2 in modulating signal transduction of G-protein coupled receptors. Specifically, co-immunoprecipitation, immunofluorescence, and confocal live-cell imaging suggest a complex containing NECAB2 and the metabotropic glutamate receptor 1 (mGluR1). In vivo measurement of phosphatidylinositol 4,5-bisphosphate further substantiates that Necab2 promotes mGluR1 signaling. Conclusions: Necab2 regulates psychomotor and social behavior via modulating a signaling cascade downstream of mGluR1.

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