TRPC4 deletion elicits behavioral defects in sociability by dysregulating expression of microRNA-138-2

The molecular changes in autism spectrum disorders (ASD) are not well understood. To investigate whether absence of transient receptor potential canonical 4 (TRPC4), which is strongly expressed in the hippocampus, affects ASD, we examined social behaviors of mice in which Trpc4 is deleted (Trpc4−/−). The Trpc4−/− mice had enhanced levels of repetitive grooming, and lowered sociability and preference for social novelty at postnatal day 56 (P56), indicative of an autism-like phenotype. In microarray analysis of hippocampus, microRNA (miR)-138-2, the precursor of miR-138, was upregulated in the Trpc4−/− mice. Absence or blockade of Trpc4 triggered Matrin3 binding to miR-138-2, thereby repressing miR-138 and raising levels of established miR-138 targets, suggesting that Trpc4 regulates signaling components opposing the development of ASD through miR-138. The autistic-like behaviors in Trpc4−/− adults were reversed by overexpressing hippocampal miR-138-2. We conclude that TRPC4 may contribute to maintain sociability through the processing of miR-138-2 for proper levels of miR-138.