Transcriptional upregulation of Cav3.2 mediates epileptogenesis in the pilocarpine model of epilepsy.
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 Ca(2+) channel Ca(v)3.2 as a central player in epileptogenesis. We show that a transient and selective upregulation of Ca(v)3.2 subunits on the mRNA and protein levels after status epilepticus causes an increase in cellular T-type Ca(2+) currents and a transitional increase in intrinsic burst firing. These functional changes are absent in mice lacking Ca(v)3.2 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(v)3.2(-/-) mice. In addition, the appearance of spontaneous seizures was dramatically reduced in these mice. Together, these data establish transcriptional induction of Ca(v)3.2 as a critical step in epileptogenesis and neuronal vulnerability.
Becker
Albert J
AJ
Departments of Neuropathology, University of Bonn Medical Center, University of Bonn, Bonn, Germany.
Pitsch
Julika
J
Sochivko
Dmitry
D
Opitz
Thoralf
T
Staniek
Matthäus
M
Chen
Chien-Chang
CC
Campbell
Kevin P
KP
Schoch
Susanne
S
Yaari
Yoel
Y
Beck
Heinz
H
D000818:Animals; D020747:Calcium Channels, T-Type / Q000235:genetics* / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics*; D053447:Channelopathies / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019599:Mossy Fibers, Hippocampal / Q000378:metabolism / Q000503:physiopathology; D018721:Muscarinic Agonists / Q000494:pharmacology; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010862:Pilocarpine / Q000494:pharmacology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015533:Transcriptional Activation / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics*
C504883:Cacna1h protein, mouse; D020747:Calcium Channels, T-Type; D018721:Muscarinic Agonists; D021122:Protein Subunits; D010862:Pilocarpine