Upregulated inwardly rectifying K<sup>+</sup> current-mediated hypoactivity of parvalbumin interneurons underlies autism-like deficits in <i>Bod1</i>-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 mechanisms behind PV ⁺ interneuron dysfunction remain largely unclear. Here, we found that a deficiency of Biorientation Defective 1 ( <i>Bod1</i>) in PV ⁺ interneurons led to an ASD-like phenotype in <i>Pvalb-Cre</i>; <i>Bod1</i> ^<i>f/f</i> mice. Mechanistically, we observed that <i>Bod1</i> deficiency induced hypoactivity of PV ⁺ interneurons and hyperactivity of calcium/calmodulin-dependent protein kinase Ⅱ alpha (CaMKⅡα) neurons in the medial prefrontal cortex, as determined by whole-cell patch-clamp recording. Additionally, <i>Bod1</i> deficiency decreased the power of high-gamma oscillation, assessed by <i>in vivo</i> multi-channel electrophysiological recording. Furthermore, we found that <i>Bod1</i> deficiency enhanced the inwardly rectifying K ⁺ current, leading to an increase in the resting membrane potential of PV ⁺ interneurons. Importantly, the gain-of-function of <i>Bod1</i> improved social deficits and stereotypical behaviors in <i>Pvalb-Cre</i>; <i>Bod1</i> ^<i>f/f</i> mice. These findings provide mechanistic insights into the PV ⁺ interneuron dysfunction and suggest new strategies for developing PV ⁺ interneuron-targeted therapies for ASD.