Li Chen, Wang Kerui, Mao Xingfeng, Sasaki Takuya, Liu Xiuxiu, Lu Yingmei
Key Laboratory of Modern Toxicology of Ministry of Education; School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
J Biomed Res. 2025 Mar 31;39(4):417-429. doi: 10.7555/JBR.38.20240394.
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 ( ) in PV interneurons led to an ASD-like phenotype in ; mice. Mechanistically, we observed that 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, deficiency decreased the power of high-gamma oscillation, assessed by multi-channel electrophysiological recording. Furthermore, we found that 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 improved social deficits and stereotypical behaviors in ; mice. These findings provide mechanistic insights into the PV interneuron dysfunction and suggest new strategies for developing PV interneuron-targeted therapies for ASD.
小清蛋白阳性（PV）中间神经元功能障碍被认为与自闭症谱系障碍（ASD）有关，ASD是一种以社交缺陷和刻板行为为特征的神经发育障碍。然而，PV中间神经元功能障碍背后的机制仍 largely 不清楚。在这里，我们发现PV中间神经元中双向定向缺陷1（ ）的缺乏导致 ； 小鼠出现ASD样表型。从机制上讲，我们观察到，通过全细胞膜片钳记录确定， 缺乏会导致内侧前额叶皮质中PV中间神经元活动不足以及钙/钙调蛋白依赖性蛋白激酶Ⅱα（CaMKⅡα）神经元活动过度。此外，通过多通道电生理记录评估， 缺乏会降低高γ振荡的功率。此外，我们发现 缺乏会增强内向整流钾电流，导致PV中间神经元静息膜电位增加。重要的是， 的功能获得改善了 ； 小鼠的社交缺陷和刻板行为。这些发现为PV中间神经元功能障碍提供了机制性见解，并为开发针对ASD的PV中间神经元靶向治疗方法提出了新策略。
