{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T19:05:49Z","timestamp":1778180749643,"version":"3.51.4"},"reference-count":70,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,13]],"date-time":"2022-07-13T00:00:00Z","timestamp":1657670400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p><jats:italic>De novo<\/jats:italic> deletion of the <jats:italic>neuronal calcium-binding protein 2<\/jats:italic> (<jats:italic>NECAB2<\/jats:italic>) locus is associated with idiopathic autism spectrum disorders (ASDs). The <jats:italic>in vivo<\/jats:italic> function of <jats:italic>NECAB2<\/jats:italic> in the brain remains largely elusive.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We investigated the morphological and behavioral profiles of both <jats:italic>necab2<\/jats:italic> knock-out and overexpression zebrafish models. The expression pattern and molecular role of <jats:italic>necab2<\/jats:italic> were probed through a combination of <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> assays.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We show that Necab2 is a neuronal specific, cytoplasmic, and membrane-associated protein, abundantly expressed in the telencephalon, habenula, and cerebellum. Necab2 is distributed peri-synaptically in subsets of glutamatergic and GABAergic neurons. CRISPR\/Cas9-generated <jats:italic>necab2<\/jats:italic> knock-out zebrafish display normal morphology but exhibit a decrease in locomotor activity and thigmotaxis with impaired social interaction only in males. Conversely, <jats:italic>necab2<\/jats:italic> 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). <jats:italic>In vivo<\/jats:italic> measurement of phosphatidylinositol 4,5-bisphosphate further substantiates that Necab2 promotes mGluR1 signaling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Necab2 regulates psychomotor and social behavior <jats:italic>via<\/jats:italic> modulating a signaling cascade downstream of mGluR1.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnmol.2022.901682","type":"journal-article","created":{"date-parts":[[2022,7,13]],"date-time":"2022-07-13T07:40:39Z","timestamp":1657698039000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Autism-Risk Gene necab2 Regulates Psychomotor and Social Behavior as a Neuronal Modulator of mGluR1 Signaling"],"prefix":"10.3389","volume":"15","author":[{"given":"Zexu","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Han","family":"Long","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianhua","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiran","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kezhe","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenchen","family":"Tao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiong","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keji","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Su","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Pi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.tins.2007.12.005","article-title":"Neuroanatomy of autism.","volume":"31","author":"Amaral","year":"2008","journal-title":"Trends Neurosci."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1186\/s12868-016-0298-z","article-title":"Identification of environmental stressors and validation of light preference as a measure of anxiety in larval zebrafish.","volume":"17","author":"Bai","year":"2016","journal-title":"BMC Neurosci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.neuro.2015.10.001","article-title":"Persistent behavioral effects following early life exposure to retinoic acid or valproic acid in zebrafish.","volume":"52","author":"Bailey","year":"2016","journal-title":"Neurotoxicology"},{"key":"B4","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1111\/j.1471-4159.2009.06348.x","article-title":"The association of metabotropic glutamate receptor type 5 with the neuronal Ca2+-binding protein 2 modulates receptor function.","volume":"111","author":"Canela","year":"2009","journal-title":"J. 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