Pathogenic MTOR somatic variant causing focal cortical dysplasia drives hyperexcitabilityviaoveractivation of neuronal GluN2C NMDA receptors

Author:

Pineau Louison,Buhler Emmanuelle,Tarhini Sarah,Bauer Sylvian,Crepel Valérie,Watrin Françoise,Cardoso Carlos,Represa Alfonso,Szepetowski Pierre,Burnashev Nail

Abstract

AbstractObjectiveGenetic variations in proteins of the mechanistic target of rapamycin (mTOR) pathway cause a spectrum of neurodevelopmental disorders often associated with brain malformations and with intractable epilepsy. The mTORopathies are characterized by hyperactive mTOR pathway and comprise tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) type II. How hyperactive mTOR translates into abnormal neuronal activity and hypersynchronous network remains to be better understood. Previously, the role of upregulated GluN2C-containing glutamate- gated NMDA receptors (NMDARs) has been demonstrated for germline defects in theTSCgenes. Here, we questioned whether this mechanism would expand to other mTORopathies in the different context of a somatic genetic variation of the MTOR protein recurrently found in FCD type II.MethodsWe used a rat model of FCD created byin uteroelectroporation of neural progenitors of dorsal telencephalon with expression vectors encoding either the wild-type or the pathogenic MTOR variant (p.S2215F). In this mosaic configuration, patch-clamp whole-cell recordings of the electroporated, spiny stellate neurons and extracellular recordings of the electroporated areas were performed in neocortical slices. Selective inhibitors were used to target mTOR activity and GluN2C- mediated currents.ResultsNeurons expressing the mutant protein displayed an excessive activation of GluN2C NMDAR-mediated spontaneous excitatory post-synaptic currents. GluN2C-dependent increase in spontaneous spiking activity was detected in the area of electroporated neurons in the mutant condition and was restricted to a critical time-window between postnatal days P9 and P20.SignificanceSomatic MTOR pathogenic variant recurrently found in FCD type II resulted in overactivation of GluN2C-mediated NMDARs in neocortices of rat pups. The related and time- restricted hyperexcitability was sensitive to subunit GluN2C-specific blockade. Our study suggests that GluN2C-related pathomechanisms might be shared in common by mTOR pathway-related cortical dysplasia.Key pointsExcessive activation of GluN2C NMDAR-mediated currents in spiny stellate neurons expressing FCD-causing MTOR somatic variationGluN2C-dependent increase in spontaneous spiking activity in rat somatosensory cortex containing mutant MTOR-expressing neuronsGluN2C-dependent excessive network activity is time-restricted to a critical period between P9 and P20

Publisher

Cold Spring Harbor Laboratory

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3