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

IF 2.2 4区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL
Chen Li, Kerui Wang, Xingfeng Mao, Xiuxiu Liu, Yingmei Lu
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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; Bod1 f/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; Bod1 f/f mice. These findings provide mechanistic insights into the PV + interneuron dysfunction and suggest new strategies for developing PV + interneuron therapies for ASD.

内向整流 K + 电流介导的副发光体中间神经元低活性上调是 Bod1 缺陷小鼠自闭症样缺陷的基础。
parvalbumin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的潜在机制仍不清楚。在这里,我们发现PV +中间神经元中双向定向缺陷1 (Bod1)的缺乏导致Pvalb-Cre中出现asd样表型;bod1f /f小鼠。在机制上,我们通过全细胞膜片钳记录发现,Bod1缺乏导致内侧前额叶皮层(mPFC)中PV +中间神经元活性降低和钙/钙调素依赖性蛋白激酶Ⅱα (CaMKⅡα)神经元活性升高。此外,根据体内多通道电生理记录的评估,它同时降低了高伽马振荡的功率。此外,我们发现Bod1缺乏增强了内向整流K +电流,导致PV +中间神经元的静息膜电位增加。重要的是,Bod1的功能获得改善了Pvalb-Cre的社会缺陷和刻板行为;bod1f /f小鼠。这些发现提供了PV +中间神经元功能障碍的机制见解,并为开发PV +中间神经元治疗ASD提供了新的策略。
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来源期刊
Journal of Biomedical Research
Journal of Biomedical Research MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
4.60
自引率
0.00%
发文量
69
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