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

Abstract

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 (Bod1) in PV⁺ interneurons led to an ASD-like phenotype in Pvalb-Cre;Bod1^f/f mice. Mechanistically, we observed that Bod1 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, Bod1 deficiency decreased the power of high-gamma oscillation, assessed by in vivo multi-channel electrophysiological recording. Furthermore, we found that Bod1 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 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-targeted therapies for ASD.

Keywords

parvalbumin neuron / biorientation defective 1 / inwardly rectifying K⁺ current / autism spectrum disorder

Fundings

This work was supported by the National Key Research and Development Program of China (Grant No. 2022YFE0108600 to Y. M. L.) and the National Natural Science Foundations of China (Grant Nos. 82473918 and 82104162 to X. X. L.).

Acknowledgments

None.

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