Pathological Networks Involving Dysmorphic Neurons in Type II Focal Cortical Dysplasia
Pathological Networks Involving Dysmorphic Neurons in Type II Focal Cortical Dysplasia
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II 型局灶性皮质发育不良涉及畸形神经元的病理网络
DOI：
10.1007/s12264-022-00828-7
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发表时间：
2022
影响因子：
5.6
通讯作者：
Jiadong Chen
中科院分区：
文献类型：
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作者：
Yijie Shao;Qianqian Ge;Jiachao Yang;Mi Wang;Yu Zhou;Jin-Xin Guo;Mengyue Zhu;Jiachen Shi;Yiqi Hu;Li Shen;Zhong Chen;Xiao-Ming Li;Jun-Ming Zhu;Jianmin Zhang;Shumin Duan;Jiadong Chen
局灶性皮质发育不良（FCD）是耐药性癫痫最常见的原因之一。畸形神经元是II型FCD的主要组织病理学特征，但其在FCD发作发生中的作用尚不清楚。本研究采用全细胞膜片钳技术对耐药癫痫患者术后脑组织皮层主要神经元进行记录和形态学重建。定量分析显示，在II型FCD的上层畸形神经元，包括一个扩大的索马，异常的树突状动脉，增加电流注入基强度动作电位放电，和减少动作电位放电频率的独特的形态和电生理特征。有趣的是，上层畸形神经元接受了减少的多巴胺能和增加的GABA能突触输入，这与Na+-K+-Cl−协同转运蛋白的上调相结合。此外，我们发现了一个去极化移位的GABA逆转电位的CamKII-cre：：PTENflox/cardiac小鼠模型的耐药性癫痫，这表明，增强GABA能输入可能去极化畸形神经元。因此，突触兴奋和抑制畸形神经元的不平衡可能有助于II型FCD癫痫发作的发生。
Focal cortical dysplasia (FCD) is one of the most common causes of drug-resistant epilepsy. Dysmorphic neurons are the major histopathological feature of type II FCD, but their role in seizure genesis in FCD is unclear. Here we performed whole-cell patch-clamp recording and morphological reconstruction of cortical principal neurons in postsurgical brain tissue from drug-resistant epilepsy patients. Quantitative analyses revealed distinct morphological and electrophysiological characteristics of the upper layer dysmorphic neurons in type II FCD, including an enlarged soma, aberrant dendritic arbors, increased current injection for rheobase action potential firing, and reduced action potential firing frequency. Intriguingly, the upper layer dysmorphic neurons received decreased glutamatergic and increased GABAergic synaptic inputs that were coupled with upregulation of the Na+-K+-Cl−cotransporter. In addition, we found a depolarizing shift of the GABA reversal potential in the CamKII-cre::PTENflox/floxmouse model of drug-resistant epilepsy, suggesting that enhanced GABAergic inputs might depolarize dysmorphic neurons. Thus, imbalance of synaptic excitation and inhibition of dysmorphic neurons may contribute to seizure genesis in type II FCD.