CaV3.2 calcium channels control NMDA receptor-mediated transmission: a new mechanism for absence epilepsy

  1. J. Julius Zhu1,9
  1. 1Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA;
  2. 2Laboratoire de Génomique Fonctionnelle, Département de Physiologie, Unité Propre de Recherche 2580, Centre National de la Recherche Scientifique, 34396 Montpellier, France;
  3. 3Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada;
  4. 4Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada;
  5. 5Department of Bioengineering, Stanford University, Stanford, California 94305, USA;
  6. 6Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA;
  7. 7Department of Psychology, University of Virginia, Charlottesville, Virginia 22908, USA;
  8. 8Department of Anesthesiology, University of Virginia, Charlottesville, Virginia 22908, USA;
  9. 9Department of Neuroscience, University of Virginia, Charlottesville, Virginia 22908, USA;
  10. 10Department of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China;
  11. 11Department of Neurology, University of Virginia, Charlottesville, Virginia 22908, USA
  1. Corresponding author: jjzhu{at}virginia.edu

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.

Keywords

Footnotes

  • Received February 22, 2015.
  • Accepted June 12, 2015.

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

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  1. doi: 10.1101/gad.260869.115 Genes & Dev. 29: 1535-1551 © 2015 Wang et al.; Published by Cold Spring Harbor Laboratory Press

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