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

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

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=15

YEAR=2022

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2022.901682

DOI=10.3389/fnmol.2022.901682

ISSN=1662-5099

ABSTRACT=<sec><title>Background</title><p><italic>De novo</italic> deletion of the <italic>neuronal calcium-binding protein 2</italic> (<italic>NECAB2</italic>) locus is associated with idiopathic autism spectrum disorders (ASDs). The <italic>in vivo</italic> function of <italic>NECAB2</italic> in the brain remains largely elusive.</p></sec><sec><title>Methods</title><p>We investigated the morphological and behavioral profiles of both <italic>necab2</italic> knock-out and overexpression zebrafish models. The expression pattern and molecular role of <italic>necab2</italic> were probed through a combination of <italic>in vitro</italic> and <italic>in vivo</italic> assays.</p></sec><sec><title>Results</title><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 <italic>necab2</italic> knock-out zebrafish display normal morphology but exhibit a decrease in locomotor activity and thigmotaxis with impaired social interaction only in males. Conversely, <italic>necab2</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). <italic>In vivo</italic> measurement of phosphatidylinositol 4,5-bisphosphate further substantiates that Necab2 promotes mGluR1 signaling.</p></sec><sec><title>Conclusions</title><p>Necab2 regulates psychomotor and social behavior <italic>via</italic> modulating a signaling cascade downstream of mGluR1.</p></sec>