Upregulated inwardly rectifying K + current-mediated hypoactivity of parvalbumin interneuron underlies autism-like deficits in Bod1-deficient mice.

Parvalbumin-positive (PV ⁺) interneuron dysfunction is believed to be linked to autism spectrum disorder (ASD), a neurodevelopmental disorder, characterized by social deficits and stereotypical behaviors. However, the underlying mechanisms of PV ⁺ interneuron dysfunction remain largely unclear. Here, we found that a deficiency of biorientation defective 1 ( Bod1) in PV ⁺ interneuron led to an ASD-like phenotype in Pvalb-Cre; Bod1 ^f/f mice. Mechanistically, we identified that Bod1 deficiency induced hypoactivity of PV ⁺ interneuron and hyperactivity of calcium/calmodulin-dependent protein kinase Ⅱ alpha (CaMKⅡα) neurons in the medial prefrontal cortex (mPFC), as determined by whole-cell patch-clamp recording. Additionally, it concurrently decreased the power of high gamma oscillation, as assessed by in vivo multi-channel electrophysiological recording. Furthermore, we found that Bod1 deficiency enhanced inwardly rectifying K ⁺ current, leading to an increase in the resting membrane potential of PV ⁺ interneurons. Importantly, the gain-of-function of Bod1 improved social deficits and stereotypical behaviors in Pvalb-Cre; Bod1 ^f/f mice. These findings provide mechanistic insights into the PV ⁺ interneuron dysfunction and suggest new strategies for developing PV ⁺ interneuron therapies for ASD.