Reduced excitatory activity in the developing mPFC mediates a PV-to-PV 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.