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

ABSTRACT: Defective social behavior and cognitive functions are hallmarks of many neurodevelopmental disorders, most notably Autism Spectrum Disorders (ASD). 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. Our findings suggest that miR-495-3p is a key downstream effector of the Tsc1/mTORC1 pathway in the control of sociability, and that targeting miR-495-3p successfully rescues aberrant gene expression patterns back to physiological control levels.

ORGANISM(S): Mus musculus

PROVIDER: GSE325693 | GEO | 2026/09/01

REPOSITORIES: GEO

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