Department of Pediatrics, Peking University First Hospital, Beijing, China.
Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases, Beijing, China.
CNS Neurosci Ther. 2019 Aug;25(8):865-875. doi: 10.1111/cns.13119. Epub 2019 Mar 20.
To reveal the pathogenesis and find the precision treatment for the childhood absence epilepsy (CAE) patients with NIPA2 mutations.
We performed whole-cell patch-clamp recordings to measure the electrophysiological properties of layer V neocortical somatosensory pyramidal neurons in wild-type (WT) and NIPA2-knockout mice.
We identified that layer V neocortical somatosensory pyramidal neurons isolated from the NIPA2-knockout mice displayed higher frequency of spontaneous and evoked action potential, broader half-width of evoked action potential, and smaller currents of BK channels than those from the WT mice. NS11021, a specific BK channel opener, reduced neuronal excitability in the NIPA2-knockout mice. Paxilline, a selective BK channel blocker, treated WT neurons and could simulate the situation of NIPA2-knockout group, thereby suggesting that the absence of NIPA2 enhanced the excitability of neocortical somatosensory pyramidal neurons by decreasing the currents of BK channels. Zonisamide, an anti-epilepsy drug, reduced action potential firing in NIPA2-knockout mice through increasing BK channel currents.
The results indicate that the absence of NIPA2 enhances neural excitability through BK channels. Zonisamide is probably a potential treatment for NIPA2 mutation-induced epilepsy, which may provide a basis for the development of new treatment strategies for epilepsy.
揭示儿童失神癫痫（CAE）伴 NIPA2 突变患者的发病机制，寻找精准治疗方法。
我们通过全细胞膜片钳记录，测量野生型（WT）和 NIPA2 敲除小鼠体感皮层 V 层神经元的电生理特性。
我们发现，与 WT 小鼠相比，NIPA2 敲除小鼠分离的体感皮层 V 层神经元具有更高频率的自发性和诱发性动作电位、更宽的诱发性动作电位半宽以及更小的 BK 通道电流。特异性 BK 通道 opener NS11021 降低了 NIPA2 敲除小鼠神经元的兴奋性。选择性 BK 通道阻滞剂 Paxilline 处理 WT 神经元可模拟 NIPA2 敲除组的情况，表明 NIPA2 的缺失通过减少 BK 通道电流增强了体感皮层 pyramidal 神经元的兴奋性。抗癫痫药物佐尼沙胺通过增加 BK 通道电流减少了 NIPA2 敲除小鼠的动作电位放电。
这些结果表明，NIPA2 的缺失通过 BK 通道增强了神经兴奋性。佐尼沙胺可能是治疗 NIPA2 突变引起癫痫的一种潜在药物，这可能为开发新的癫痫治疗策略提供依据。
