Zhijuan Zhang1 · Hui Zhang1 · Ana Antonic‑Baker3 · Patrick Kwan1,3 · Yin Yan2 · Yuanlin Ma11 Department of Neurology, Chongqing Key Laboratory of Neurology, The First Afliated Hospital of Chongqing Medical University, Chongqing 400016, China
2 Chongqing Emergency Medical Center, The First Afliated Hospital of Chongqing Medical University, Chongqing 400016, China
3 Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia
Abstract
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.
Keywords
Epilepsy; CXCR5 ; Embryonic neurogenesis; Pluripotent stem cells; Intrauterine electroporation; F-actin; Neuronal polarity; Neuronal migration
