Department of Neurology, Chongqing Key Laboratory of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia.
Neurosci Bull. 2023 Nov;39(11):1605-1622. doi: 10.1007/s12264-023-01087-w. Epub 2023 Jul 17.
Epilepsy is a common, chronic neurological disorder that has been associated with impaired neurodevelopment and immunity. The chemokine receptor CXCR5 is involved in seizures via an unknown mechanism. Here, we first determined the expression pattern and distribution of the CXCR5 gene in the mouse brain during different stages of development and the brain tissue of patients with epilepsy. Subsequently, we found that the knockdown of CXCR5 increased the susceptibility of mice to pentylenetetrazol- and kainic acid-induced seizures, whereas CXCR5 overexpression had the opposite effect. CXCR5 knockdown in mouse embryos via viral vector electrotransfer negatively influenced the motility and multipolar-to-bipolar transition of migratory neurons. Using a human-derived induced an in vitro multipotential stem cell neurodevelopmental model, we determined that CXCR5 regulates neuronal migration and polarization by stabilizing the actin cytoskeleton during various stages of neurodevelopment. Electrophysiological experiments demonstrated that the knockdown of CXCR5 induced neuronal hyperexcitability, resulting in an increased number of seizures. Finally, our results suggested that CXCR5 deficiency triggers seizure-related electrical activity through a previously unknown mechanism, namely, the disruption of neuronal polarity.
癫痫是一种常见的慢性神经障碍，与神经发育和免疫受损有关。趋化因子受体 CXCR5 通过未知机制参与癫痫发作。在这里，我们首先确定了 CXCR5 基因在不同发育阶段的小鼠大脑和癫痫患者脑组织中的表达模式和分布。随后，我们发现 CXCR5 的敲低会增加小鼠对戊四氮和海人酸诱导的癫痫发作的易感性，而 CXCR5 的过表达则有相反的效果。通过病毒载体电转将 CXCR5 敲低到小鼠胚胎中会对迁移神经元的运动和多极到两极的转变产生负面影响。使用源自人类的诱导多潜能干细胞神经发育模型，我们确定 CXCR5 通过在神经发育的各个阶段稳定肌动蛋白细胞骨架来调节神经元迁移和极化。电生理实验表明，CXCR5 的敲低导致神经元过度兴奋，从而导致癫痫发作次数增加。最后，我们的结果表明，CXCR5 缺失通过一种未知的机制触发与癫痫相关的电活动，即神经元极性的破坏。
