[논문]Non–Cell Autonomous Epileptogenesis in Focal Cortical Dysplasia

Koh, Hyun Yong; Jang, Jaeson; Ju, Sang Hyeon; Kim, Ryunhee; Cho, Gyu‐; Bon; Kim, Dong Seok; Sohn, Jong‐; Woo; Paik, Se‐; Bum; Lee, Jeong Ho

doi:10.1002/ana.26149

[해외논문] Non–Cell Autonomous Epileptogenesis in Focal Cortical Dysplasia

Annals of neurology, v.90 no.2, 2021년, pp.285 - 299

Koh, Hyun Yong (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea) , Jang, Jaeson (Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea) , Ju, Sang Hyeon (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea) , Kim, Ryunhee (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea) , Cho, Gyu‐Bon (Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea) , Kim, Dong Seok (Department of Neurosurgery, Pediatric Epilepsy Clinics, Brain Korea 21 Project for Medical Science, Severance Children's Hospital, Yonsei University College of Medicine, Seo) , Sohn, Jong‐Woo , Paik, Se‐Bum , Lee, Jeong Ho

Abstract ▼ AI-Helper

ObjectiveLow‐level somatic mosaicism in the brain has been shown to be a major genetic cause of intractable focal epilepsy. However, how a relatively few mutation‐carrying neurons are able to induce epileptogenesis at the local network level remains poorly understood.MethodsTo probe the origin of epileptogenesis, we measured the excitability of neurons with MTOR mutation and nearby nonmutated neurons recorded by whole‐cell patch‐clamp and array‐based electrodes comparing the topographic distribution of mutation. Computational simulation is used to understand neural network‐level changes based on electrophysiological properties. To examine the underlying mechanism, we measured inhibitory and excitatory synaptic inputs in mutated neurons and nearby neurons by electrophysiological and histological methods using the mouse model and postoperative human brain tissue for cortical dysplasia. To explain non–cell‐autonomous hyperexcitability, an inhibitor of adenosine kinase was injected into mice to enhance adenosine signaling and to mitigate hyperactivity of nearby nonmutated neurons.ResultsWe generated mice with a low‐level somatic mutation in MTOR presenting spontaneous seizures. The seizure‐triggering hyperexcitability originated from nonmutated neurons near mutation‐carrying neurons, which proved to be less excitable than nonmutated neurons. Interestingly, the net balance between excitatory and inhibitory synaptic inputs onto mutated neurons remained unchanged. Additionally, we found that inhibition of adenosine kinase, which affects adenosine metabolism and neuronal excitability, reduced the hyperexcitability of nonmutated neurons.InterpretationThis study shows that neurons carrying somatic mutations in MTOR lead to focal epileptogenesis via non–cell‐autonomous hyperexcitability of nearby nonmutated neurons. ANN NEUROL 2021;90:285–299

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