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The Journal of Neuroscience, December 3, 2008, 28(49):13341-13353; doi:10.1523/JNEUROSCI.1421-08.2008

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Neurobiology of Disease
Transcriptional Upregulation of Ca_v3.2 Mediates Epileptogenesis in the Pilocarpine Model of Epilepsy

Albert J. Becker,¹ Julika Pitsch,¹ Dmitry Sochivko,² Thoralf Opitz,² Matthäus Staniek,^2,3 Chien-Chang Chen,⁴ Kevin P. Campbell,⁴ Susanne Schoch,¹ Yoel Yaari,⁵ and Heinz Beck²

Departments of ¹Neuropathology and ²Epileptology, University of Bonn Medical Center, and ³Helmholtz Institute for Radiation and Nuclear Physics, University of Bonn, 53105 Bonn, Germany, ⁴Howard Hughes Medical Institute for Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52242, and ⁵Department of Physiology, Hebrew University–Hadassah School of Medicine, 91120 Jerusalem, Israel

Correspondence should be addressed to Dr. Heinz Beck, Department of Epileptology, University of Bonn Medical Center, Sigmund-Freud Strasse 25, D-53105 Bonn, Germany. Email: heinz.beck{at}ukb.uni-bonn.de

In both humans and animals, an insult to the brain can lead, after a variable latent period, to the appearance of spontaneous epileptic seizures that persist for life. The underlying processes, collectively referred to as epileptogenesis, include multiple structural and functional neuronal alterations. We have identified the T-type Ca²⁺ channel Ca_v3.2 as a central player in epileptogenesis. We show that a transient and selective upregulation of Ca_v3.2 subunits on the mRNA and protein levels after status epilepticus causes an increase in cellular T-type Ca²⁺ currents and a transitional increase in intrinsic burst firing. These functional changes are absent in mice lacking Ca_v3.2 subunits. Intriguingly, the development of neuropathological hallmarks of chronic epilepsy, such as subfield-specific neuron loss in the hippocampal formation and mossy fiber sprouting, was virtually completely absent in Ca_v3.2^–/– mice. In addition, the appearance of spontaneous seizures was dramatically reduced in these mice. Together, these data establish transcriptional induction of Ca_v3.2 as a critical step in epileptogenesis and neuronal vulnerability.

Key words: plasticity; burst discharge; epileptogenesis; reorganization; channelopathy; temporal lobe epilepsy

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Received April 3, 2008; revised Oct. 11, 2008; accepted Oct. 22, 2008.

Correspondence should be addressed to Dr. Heinz Beck, Department of Epileptology, University of Bonn Medical Center, Sigmund-Freud Strasse 25, D-53105 Bonn, Germany. Email: heinz.beck{at}ukb.uni-bonn.de

This article has been cited by other articles:

				J. D. Graef, B. K. Nordskog, W. F. Wiggins, and D. W. Godwin An Acquired Channelopathy Involving Thalamic T-Type Ca2+ Channels after Status Epilepticus J. Neurosci., April 8, 2009; 29(14): 4430 - 4441. [Abstract] [Full Text] [PDF]

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