Reduced excitatory activity in the developing mPFC mediates a PV H -to-PV L transition and impaired social cognition in autism spectrum disorders.

Understanding the neuropathogenesis of impaired social cognition in autism spectrum disorders (ASD) is challenging. Altered cortical parvalbumin-positive (PV + ) interneurons have been consistently observed in ASD, but their roles and the underlying mechanisms remain poorly understood. In our study, we observed a downward-shifted spectrum of PV expression in the developing medial prefrontal cortex (mPFC) of ASD mouse models due to decreased activity of PV + neurons. Surprisingly, chemogenetically suppressing PV + neuron activity during postnatal development failed to induce ASD-like behaviors. In contrast, lowering excitatory activity in the developing mPFC not only dampened the activity state and PV expression of individual PV + neurons, but also replicated ASD-like social deficits. Furthermore, enhancing excitation, but not PV + interneuron-mediated inhibition, rescued social deficits in ASD mouse models. Collectively, our findings propose that reduced excitatory activity in the developing mPFC may serve as a shared local circuitry mechanism triggering alterations in PV + interneurons and mediating impaired social functions in ASD.