Induced Overexpression of Connexin43 in Astrocytes Attenuates the Progression of Experimental Temporal Lobe Epilepsy

IF 3.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Oussama Kherbouche, Lukas Henning, Pia Niemann, Caroline Geisen, Gerald Seifert, Christian Henneberger, Bernd K. Fleischmann, Christian Steinhäuser, Peter Bedner
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引用次数: 0

Abstract

Astrocytic gap junctional communication plays a critical role in regulating neuronal activity and network synchronization, yet its precise contributions to brain function and the pathogenesis of neurological disorders remains incompletely understood. To address this, we generated a transgenic mouse line with inducible, astrocyte-specific overexpression of the gap junction protein connexin43 (Cx43). In these mice, hippocampal astrocytes exhibited markedly elevated Cx43 protein levels and a ~ 20% increase in intercellular gap junction coupling. Enhanced coupling was accompanied by a reduction in astrocytic cell volume and branching, without affecting passive membrane properties or astrocyte density in the hippocampus. Cx43 overexpression had no detectable impact on adult neurogenesis in the dentate gyrus, nor did it alter hippocampal synaptic efficacy or plasticity. Notably, in a mouse model of temporal lobe epilepsy with hippocampal sclerosis, astrocytic Cx43 overexpression attenuated chronic epileptic activity and the extent of sclerosis, supporting an antiepileptic role of the astroglial network. Collectively, these findings enhance our understanding of the functional relevance of astrocytic gap junction coupling in health and disease, with potential implications for the design of new treatment strategies.

星形胶质细胞诱导的连接蛋白43过表达可减弱实验性颞叶癫痫的进展
星形胶质细胞间隙连接通信在调节神经元活动和网络同步中起着关键作用,但其对脑功能和神经疾病发病机制的确切贡献仍不完全清楚。为了解决这个问题,我们产生了一个转基因小鼠系,诱导的,星形胶质细胞特异性过表达间隙连接蛋白connexin43 (Cx43)。在这些小鼠中,海马星形胶质细胞表现出Cx43蛋白水平显著升高,细胞间隙连接偶联增加约20%。偶联增强伴随着星形胶质细胞体积和分支的减少,而不影响被动膜特性或海马星形胶质细胞密度。Cx43过表达对齿状回的成人神经发生没有可检测到的影响,也没有改变海马突触的功效或可塑性。值得注意的是,在伴有海马硬化的颞叶癫痫小鼠模型中,星形胶质细胞Cx43过表达减轻了慢性癫痫活动和硬化程度,支持星形胶质网络的抗癫痫作用。总的来说,这些发现增强了我们对星形细胞间隙连接偶联在健康和疾病中的功能相关性的理解,对设计新的治疗策略具有潜在的意义。
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来源期刊
Neurochemical Research
Neurochemical Research 医学-神经科学
CiteScore
7.70
自引率
2.30%
发文量
320
审稿时长
6 months
期刊介绍: Neurochemical Research is devoted to the rapid publication of studies that use neurochemical methodology in research on nervous system structure and function. The journal publishes original reports of experimental and clinical research results, perceptive reviews of significant problem areas in the neurosciences, brief comments of a methodological or interpretive nature, and research summaries conducted by leading scientists whose works are not readily available in English.
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