The inhibition of miR-495-3p rescues Tsc1 knockdown-driven RNA expression changes

We have identified the miR-379-410 cluster, the largest placental mammal-specific miRNA cluster, as a critical molecular brake on sociability. In this study, we utilized transient hippocampal knockdown (KD) of the ASD risk gene Tsc1, a key negative regulator of mTORC1, as a mouse model of autism-like behavior.

Molecularly, Tsc1 KD leads to the upregulation of the miR-379-410 member, miR-495-3p. We found that the inhibition of this miRNA by a Locked Nucleic Acid(LNA)-modified antisense oligonucleotide was sufficient to prevent Tsc1 KD-induced hyposociability and memory impairments. To investigate the underlying transcriptomic changes, we assessed gene expression patterns in mouse hippocampi injected with either a control short hairpin, a Tsc1 short hairpin (shTsc1), or a combination of shTsc1 and a LNA against miR-495-3p.