Early Postnatal Dysfunction of mPFC PV Interneurons in Shank3B ^−/− Mice

Medial prefrontal cortex (mPFC) dysfunction is associated with cognitive and sensory abnormalities in individuals with autism spectrum disorder (ASD) , yet the trajectory of mPFC circuit development in these conditions remains poorly understood. In this study, we investigated the postnatal maturation of glutamatergic connectivity and neuronal excitability in pyramidal neurons (PYR) and parvalbumin-positive interneurons (PVIN) in the mPFC of mice harboring deletions in SHANK3, a well-established genetic cause of autism associated with severe cognitive impairments and seizures. Our findings reveal early deficits in PVIN excitability that precede changes in the synaptic and intrinsic properties of PYR, resulting in impaired feedforward inhibition. In vivo calcium imaging demonstrated hypoactivity of PVIN in dorsal mPFC circuits during early postnatal development, characterized by reduced frequency of calcium transients. By adulthood, excitability phenotypes were reversed, with PVIN becoming hyperexcitable and PYR hypoexcitable. These results suggest that PVIN dysfunction in Shank3B ^−/− mice emerges during postnatal development and may represent a key pathogenic mechanism and potential therapeutic target in SHANK3-related disorders.