Epilepsy is a common neurological disorder, which has been linked to mutations or deletions of RNA binding protein, fox-1 homolog ( Caenorhabditis elegans ) 3 ( RBFOX3 )/ NeuN , a neuronal splicing regulator. However, the mechanism of seizure mediation by RBFOX3 remains unknown. Here, we show that mice with deletion of Rbfox3 in gamma-aminobutyric acid (GABA) ergic neurons exhibit spontaneous seizures and high premature mortality due to increased presynaptic release, postsynaptic potential, neuronal excitability, and synaptic transmission in hippocampal dentate gyrus granule cells (DGGCs). Attenuating early excitatory gamma-aminobutyric acid (GABA) action by administering bumetanide, an inhibitor of early GABA depolarization, rescued premature mortality. Rbfox3 deletion reduced hippocampal expression of vesicle-associated membrane protein 1 (VAMP1), a GABAergic neuron-specific presynaptic protein. Postnatal restoration of VAMP1 rescued premature mortality and neuronal excitability in DGGCs. Furthermore, Rbfox3 deletion in GABAergic neurons showed fewer neuropeptide Y (NPY)–expressing GABAergic neurons. In addition, deletion of Rbfox3 in NPY-expressing GABAergic neurons lowered intrinsic excitability and increased seizure susceptibility. Our results establish RBFOX3 as a critical regulator and possible treatment path for epilepsy.

中文翻译：

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神经元剪接调节剂 RBFOX3 通过优先调节表达 NPY 的 GABAergic 神经元中的 Vamp1 表达来介导癫痫发作

癫痫是一种常见的神经系统疾病，与 RNA 结合蛋白 fox-1 同系物的突变或缺失有关（秀丽隐杆线虫) 3 (RBFOX3)/神经元, 一种神经元剪接调节剂。然而，RBFOX3 介导癫痫发作的机制仍然未知。在这里，我们展示了删除了Rbfox3在 γ-氨基丁酸 (GABA) 能神经元中，由于海马齿状回颗粒细胞 (DGGCs) 中突触前释放、突触后电位、神经元兴奋性和突触传递增加，导致自发性癫痫发作和高过早死亡率。通过给予早期 GABA 去极化抑制剂布美他尼减弱早期兴奋性γ-氨基丁酸 (GABA) 作用，挽救了过早死亡。Rbfox3缺失降低了囊泡相关膜蛋白 1 (VAMP1) 的海马表达，这是一种 GABA 能神经元特异性突触前蛋白。VAMP1 的产后恢复挽救了 DGGC 中的过早死亡和神经元兴奋性。此外，Rbfox3GABA 能神经元的缺失表明表达神经肽 Y (NPY) 的 GABA 能神经元较少。此外，删除Rbfox3在表达 NPY 的 GABA 能神经元中，内在兴奋性降低，癫痫发作易感性增加。我们的结果将 RBFOX3 确定为癫痫的关键调节剂和可能的治疗途径。