title: CaV3.2 calcium channels control NMDA receptor-mediated transmission: a new mechanism for absence epilepsy.
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.
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA;
authors.forename: Guangfu
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA;
authors.forename: Genrieta
authors.initials: G
authors.lastname: Bochorishvili
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA;
authors.forename: Yucai
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA;
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Salvati
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA;
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Laboratoire de Génomique Fonctionnelle, Département de Physiologie, Unité Propre de Recherche 2580, Centre National de la Recherche Scientifique, 34396 Montpellier, France;
authors.forename: Steve J
authors.initials: SJ
authors.lastname: Dubel
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA;
authors.forename: Edward
authors.initials: E
authors.lastname: Perez-Reyes
authors.affiliation: Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada; Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada;
authors.forename: Terrance P
authors.initials: TP
authors.lastname: Snutch
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA;
authors.forename: Ruth L
authors.initials: RL
authors.lastname: Stornetta
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, California 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA;
authors.forename: Karl
authors.initials: K
authors.lastname: Deisseroth
authors.affiliation: Department of Psychology, University of Virginia, Charlottesville, Virginia 22908, USA;
authors.forename: Alev
authors.initials: A
authors.lastname: Erisir
authors.affiliation: Department of Anesthesiology, University of Virginia, Charlottesville, Virginia 22908, USA; Department of Neuroscience, University of Virginia, Charlottesville, Virginia 22908, USA;
authors.forename: Slobodan M
authors.initials: SM
authors.lastname: Todorovic
authors.affiliation: Department of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China;
authors.forename: Jian-Hong
authors.initials: JH
authors.lastname: Luo
authors.affiliation: Department of Neurology, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Jaideep
authors.initials: J
authors.lastname: Kapur
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA;
authors.forename: Mark P
authors.initials: MP
authors.lastname: Beenhakker
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA; Department of Neuroscience, University of Virginia, Charlottesville, Virginia 22908, USA;
authors.forename: J Julius
authors.initials: JJ
authors.lastname: Zhu
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000235:genetics* / Q000378:metabolism*; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000378:metabolism; D004832:Epilepsy, Absence / Q000235:genetics / Q000503:physiopathology*; D005786:Gene Expression Regulation; D006801:Humans; D009154:Mutation; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000378:metabolism
chemical_list: C479952:CACNA1H protein, human; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020747:Calcium Channels, T-Type; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins
keywords: CaV3.2 channels; NMDA transmission; childhood absence epilepsy; synapses