한빛사논문
- 조회848
Hyun Yong Koh M.D. Ph.D.1,8,10,11, Jaeson Jang Ph.D.2,8, Sang Hyeon Ju M.D.1,8, Ryunhee Kim Ph.D.1, Gyu-Bon Cho M.S.3,12, Dong Seok Kim M.D. Ph.D.4, Jong-Woo Sohn M.D. Ph.D.3,*, Se-Bum Paik Ph.D.2,5,*, Jeong Ho Lee M.D. Ph.D.1,6,7,9,*
1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea.
2Department of Bio and Brain Engineering, KAIST, Daejeon, 34141, Republic of Korea.
3Department of Biological Sciences, KAIST, Daejeon, 34141, Republic of Korea.
4Department of Neurosurgery, Pediatric Epilepsy Clinics, Brain Korea 21 project for medical cience, Severance Children’s Hospital, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
5Program of Brain and Cognitive Engineering, KAIST, Daejeon, 34141, Republic of Korea.
6Biomedical Science and Engineering Interdisciplinary Program, KAIST, Daejeon, 34141, Republic of Korea.
7SoVarGen, Inc., Daejeon, 34051, Republic of Korea.
8These authors contributed equally.
9Lead contact
Current position: 10Epilepsy Genetics Program, Department of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA., 11The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, MA, USA., 12Toolgen, Inc., Seoul, 08501, Republic of Korea.
*Corresponding Authors. These authors jointly supervised this work.
Abstract
Objective
Low-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.
Methods
To probe the origin of epileptogenesis, we measured the excitability of neurons with MTOR mutation and nearby non-mutated 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 non-mutated neurons.
Results
We generated mice having a low-level somatic mutation in MTOR presenting spontaneous seizures. The seizure-triggering hyperexcitability was originated from non-mutated neurons near mutation-carrying neurons which proved to be less excitable than non-mutated 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 non-mutated neurons.
Interpretation
This study showed that neurons carrying somatic mutations in MTOR lead to focal epileptogenesis via non-cell autonomous hyperexcitability of nearby non-mutated neurons.
논문정보
- Research article
- 2021년 06월 (BRIC 등록일 2021-07-08)
- 국내 연구진
- 의약학 > 신경의학
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