Non-Cell Autonomous Epileptogenesis in Focal Cortical Dysplasia
Non-Cell Autonomous Epileptogenesis in Focal Cortical Dysplasia
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DOI：
10.1002/ana.26149
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发表时间：
2021-07-16
影响因子：
11.2
通讯作者：
Lee, Jeong Ho
中科院分区：
文献类型：
--
作者：
Koh, Hyun Yong;Jang, Jaeson;Lee, Jeong Ho
目的低水平的脑体嵌合体是顽固性局灶性癫痫的主要遗传原因。然而，相对较少的携带突变的神经元如何能够在局部网络水平上诱导癫痫发生仍然知之甚少。方法通过全细胞膜片钳和阵列电极记录MTOR突变神经元和附近非突变神经元的兴奋性，比较突变的地形分布，探讨癫痫发生的起源。计算模拟用于理解基于电生理特性的神经网络级变化。为了研究潜在的机制，我们使用小鼠模型和皮质发育不良术后的人脑组织，通过电生理和组织学方法测量了突变神经元和附近神经元的抑制性和兴奋性突触输入。为了解释非细胞自主的高兴奋性，一种腺苷激酶抑制剂被注射到小鼠体内，以增强腺苷信号并减轻附近非突变神经元的过度活跃。结果制备的MTOR低水平体细胞突变小鼠呈现自发性癫痫发作。癫痫触发的高兴奋性来源于携带突变的神经元附近的非突变神经元，而携带突变的神经元比未突变的神经元更容易兴奋。有趣的是，突变神经元的兴奋性和抑制性突触输入之间的净平衡保持不变。此外，我们发现抑制腺苷激酶会影响腺苷代谢和神经元兴奋性，从而降低非突变神经元的高兴奋性。本研究表明，携带MTOR体细胞突变的神经元通过附近非突变神经元的非细胞自主高兴奋性导致局灶性癫痫发生。Ann neurol 2021
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