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.