Chen Li, Kerui Wang, Xingfeng Mao, Xiuxiu Liu, Yingmei Lu
{"title":"Upregulated inwardly rectifying K <sup>+</sup> current-mediated hypoactivity of parvalbumin interneuron underlies autism-like deficits in <i>Bod1</i>-deficient mice.","authors":"Chen Li, Kerui Wang, Xingfeng Mao, Xiuxiu Liu, Yingmei Lu","doi":"10.7555/JBR.38.20240394","DOIUrl":null,"url":null,"abstract":"<p><p>Parvalbumin-positive (PV <sup>+</sup>) 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 <sup>+</sup> interneuron dysfunction remain largely unclear. Here, we found that a deficiency of biorientation defective 1 ( <i>Bod1</i>) in PV <sup>+</sup> interneuron led to an ASD-like phenotype in <i>Pvalb-Cre</i>; <i>Bod1</i> <sup><i>f/f</i></sup> mice. Mechanistically, we identified that <i>Bod1</i> deficiency induced hypoactivity of PV <sup>+</sup> 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 <i>in vivo</i> multi-channel electrophysiological recording. Furthermore, we found that <i>Bod1</i> deficiency enhanced inwardly rectifying K <sup>+</sup> current, leading to an increase in the resting membrane potential of PV <sup>+</sup> interneurons. Importantly, the gain-of-function of <i>Bod1</i> improved social deficits and stereotypical behaviors in <i>Pvalb-Cre</i>; <i>Bod1</i> <sup><i>f/f</i></sup> mice. These findings provide mechanistic insights into the PV <sup>+</sup> interneuron dysfunction and suggest new strategies for developing PV <sup>+</sup> interneuron therapies for ASD.</p>","PeriodicalId":15061,"journal":{"name":"Journal of Biomedical Research","volume":" ","pages":"1-13"},"PeriodicalIF":2.2000,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Biomedical Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.7555/JBR.38.20240394","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
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 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; Bod1f/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; Bod1f/f mice. These findings provide mechanistic insights into the PV + interneuron dysfunction and suggest new strategies for developing PV + interneuron therapies for ASD.