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 mech...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;Bod1f/f mice.Mechanistically,we observed that Bod1 deficiency induced hypoactivity of PV^(+)interneurons and hyperactivity of calcium/calmodulin-dependent protein kinaseⅡalpha(CaMKⅡα)neurons in the medial prefrontal cortex,as determined by whole-cell patch-clamp recording.Additionally,Bod1 deficiency decreased the power of highgamma 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;Bod1f/f mice.These findings provide mechanistic insights into the PV^(+)interneuron dysfunction and suggest new strategies for developing PV^(+)interneuron-targeted therapies for ASD.展开更多
基金supported by the National Key Research and Development Program of China(Grant No.2022YFE0108600 to Y.M.L.)the National Natural Science Foundations of China(Grant Nos.82473918 and 82104162 to X.X.L.).
文摘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;Bod1f/f mice.Mechanistically,we observed that Bod1 deficiency induced hypoactivity of PV^(+)interneurons and hyperactivity of calcium/calmodulin-dependent protein kinaseⅡalpha(CaMKⅡα)neurons in the medial prefrontal cortex,as determined by whole-cell patch-clamp recording.Additionally,Bod1 deficiency decreased the power of highgamma 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;Bod1f/f mice.These findings provide mechanistic insights into the PV^(+)interneuron dysfunction and suggest new strategies for developing PV^(+)interneuron-targeted therapies for ASD.
