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

Background: deletion of the () locus is associated with idiopathic autism spectrum disorders (ASDs). The function of in the brain remains largely elusive.

Methods: We investigated the morphological and behavioral profiles of both knock-out and overexpression zebrafish models. The expression pattern and molecular role of were probed through a combination of and 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 peri-synaptically in subsets of glutamatergic and GABAergic neurons. CRISPR/Cas9-generated knock-out zebrafish display normal morphology but exhibit a decrease in locomotor activity and thigmotaxis with impaired social interaction only in males. Conversely, 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). measurement of phosphatidylinositol 4,5-bisphosphate further substantiates that Necab2 promotes mGluR1 signaling.

Conclusions: Necab2 regulates psychomotor and social behavior modulating a signaling cascade downstream of mGluR1.