miR-495-3p inhibition rescues mTORC1 hyperactivation-driven autistic-like behaviors in mice

Abstract Defective social behavior and cognitive functions are hallmarks of Autism spectrum disorders (ASD). The molecular mechanisms keeping social behavior in a physiological range are largely unknown. We recently found that conditional knockout (cKO) of tmiRNA cluster miR-379-410 in mouse hippocampal neurons leads to hypersocial behavior. Therefore, inhibiting miR-379-410 members might represent a strategy to promote sociability in ASD. As an ASD model, we chose knockdown (KD) of the ASD risk gene Tsc1, a key negative regulator of mTORC1. Acute Tsc1 knockdown (KD) in hippocampal neurons was sufficient to induce hyposociability and memory deficits in adult wild-type mice. In contrast, Tsc1 KD had no effect on sociability in miR-379-410 cKO mice, indicating a requirement of miR-379-410. Furthermore, Tsc1 KD led to upregulation of tmiR-495-3p, and inhibition of this miRNA by antisense oligonucleotides was sufficient to prevent hyposociability and memory impairments. Our findings suggest that miR-495-3p is a key downstream effector of the Tsc1/mTORC1 pathway in sociability, and that targeting miR-495-3p represents a therapeutic avenue for restoring social and cognitive impairments in ASD without affecting mTORC1 homeostasis.