Author:
Wang Guangfu,Bochorishvili Genrieta,Chen Yucai,Salvati Kathryn A.,Zhang Peng,Dubel Steve J.,Perez-Reyes Edward,Snutch Terrance P.,Stornetta Ruth L.,Deisseroth Karl,Erisir Alev,Todorovic Slobodan M.,Luo Jian-Hong,Kapur Jaideep,Beenhakker Mark P.,Zhu J. Julius
Abstract
CaV3.2 T-type calcium channels, encoded by CACNA1H, are expressed throughout the brain, yet their general function remains unclear. We discovered that CaV3.2 channels control NMDA-sensitive glutamatergic receptor (NMDA-R)-mediated transmission and subsequent NMDA-R-dependent plasticity of AMPA-R-mediated transmission at rat central synapses. Interestingly, functional CaV3.2 channels primarily incorporate into synapses, replace existing CaV3.2 channels, and can induce local calcium influx to control NMDA transmission strength in an activity-dependent manner. Moreover, human childhood absence epilepsy (CAE)-linked hCaV3.2(C456S) mutant channels have a higher channel open probability, induce more calcium influx, and enhance glutamatergic transmission. Remarkably, cortical expression of hCaV3.2(C456S) channels in rats induces 2- to 4-Hz spike and wave discharges and absence-like epilepsy characteristic of CAE patients, which can be suppressed by AMPA-R and NMDA-R antagonists but not T-type calcium channel antagonists. These results reveal an unexpected role of CaV3.2 channels in regulating NMDA-R-mediated transmission and a novel epileptogenic mechanism for human CAE.
Funder
National Institutes of Health
Epilepsy Foundation
Howard Hughes Medical Institute
National Basic Research Program of China
Natural Science Foundation of China
Canadian Institutes of Health Research
Canada Research Chair in Biotechnology and Genomics-Neurology
Publisher
Cold Spring Harbor Laboratory
Subject
Developmental Biology,Genetics
Cited by
45 articles.
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