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Pathologically activated GABAA α3 receptors underlie autism-like features

ABSTRACT: Social deficits and repetitive behaviors define autism spectrum disorder (ASD), yet their shared underlying mechanisms remain elusive. Here we uncover a convergent pathophysiological mechanism across multiple ASD models. We found that GABAergic neurons in the dorsal raphe nucleus (DRNGABA neurons) are hyperactive in Shank3B–/– mice. Chemogenetic activation of these neurons recapitulated ASD-like behaviors, whereas inhibition reversed them. Shank3 knockdown in DRNGABA neurons phenocopied ASD-related changes through upregulation of ErbB4-mGluR1/5 signaling. Sustained DRNGABA hyperactivity drove the pathological recruitment of postsynaptic GABAA α3 receptors, resulting in hypoactivity of DRN5-HT neurons. Gabra3 knockdown in DRN5-HT neurons rescued behavioral deficits in Shank3B–/– mice. Notably, systemic low-dose bicuculline—selectively inhibiting GABAA α3 receptors—ameliorated core ASD-like behaviors across multiple etiologically distinct models, including Shank3B–/– mice, offspring of Poly: IC-injected dams, and BTBR mice, without affecting basal transmission. Together, these findings identify pathologically activated GABAA α3 receptors as a convergent therapeutic target for ASD.

ORGANISM(S): Mus Musculus

SUBMITTER: Xinhong Zhu

PROVIDER: PXD076235 | iProX | Fri Mar 27 00:00:00 GMT 2026

REPOSITORIES: iProX

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