Pathological Networks Involving Dysmorphic Neurons in Type II Focal Cortical Dysplasia
Yijie Shao1,2 • Qianqian Ge1 • Jiachao Yang1 • Mi Wang1 • Yu Zhou1 • Jin-Xin Guo3 • Mengyue Zhu1 • Jiachen Shi1 • Yiqi Hu1 • Li Shen3,4,5 • Zhong Chen6,7 • Xiao-Ming Li8,9 • Jun-Ming Zhu2 • Jianmin Zhang2 • Shumin Duan1 • Jiadong Chen1 Center for Neuroscience and Department of Neurosurgery of the Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China
2 Department of Neurosurgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
3 The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
4 Department of Orthopedic Surgery, School of Medicine, the Second Affiliated Hospital, Zhejiang University, Hangzhou 310009, China
5 Hangzhou Innovation Center, Zhejiang University, Hangzhou 310058, China
6 Institute of Pharmacology & Toxicology, NHC and CAMS Key Laboratory of Medical Neurobiology, College of Pharmaceutical Sciences, School of Basic Medical Sciences, Zhejiang University, Hangzhou 310058, China
7 Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310058, China
8 Center for Neuroscience and Department of Neurology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
9 NHC and CAMS Key Laboratory of Medical Neurobiology, Center for Brain Science and Brain-Inspired Intelligence, Joint Institute for Genetics and Genome Medicine between, Guangdong Hong Kong Macao Greater Bay Area, Zhejiang University and the University of Toronto, Zhejiang University School of Medicine, Hangzhou 310058, China
Abstract
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/flox mouse 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.
Keywords
Focal cortical dysplasia; Dysmorphic neuron; Whole-cell patch-clamp recording; Morphological reconstruction; Excitation-inhibition balance
