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Non–Cell Autonomous Epileptogenesis in Focal Cortical Dysplasia
Author(s) -
Koh Hyun Yong,
Jang Jaeson,
Ju Sang Hyeon,
Kim Ryunhee,
Cho GyuBon,
Kim Dong Seok,
Sohn JongWoo,
Paik SeBum,
Lee Jeong Ho
Publication year - 2021
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.26149
Subject(s) - epileptogenesis , neuroscience , inhibitory postsynaptic potential , excitatory postsynaptic potential , cortical dysplasia , electrophysiology , biology , adenosine kinase , somatic cell , adenosine , epilepsy , neuron , endocrinology , gene , genetics , adenosine deaminase
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 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. Results We 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. Interpretation This 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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