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The Journal of Neuroscience, April 8, 2009, 29(14):4430-4441; doi:10.1523/JNEUROSCI.0198-09.2009

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Neurobiology of Disease
An Acquired Channelopathy Involving Thalamic T-Type Ca²⁺ Channels after Status Epilepticus

John D. Graef,^1,2 Brian K. Nordskog,¹ Walter F. Wiggins,¹ and Dwayne W. Godwin^1,2

¹Department of Neurobiology and Anatomy, and ²The Neuroscience Program, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

Correspondence should be addressed to Dr. Dwayne W. Godwin, Department of Neurobiology and Anatomy, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27127. Email: dgodwin{at}wfubmc.edu

Some epilepsies are linked to inherited traits, but many appear to arise through acquired alterations in neuronal excitability. Status epilepticus (SE) is associated with numerous changes that promote spontaneous recurrent seizures (SRS), and studies have suggested that hippocampal T-type Ca²⁺ channels underlie increased bursts of activity integral to the generation of these seizures. The thalamus also contributes to epileptogenesis, but no studies have directly assessed channel alterations in the thalamus during SE or subsequent periods of SRS. We therefore investigated longitudinal changes in thalamic T-type channels in a mouse pilocarpine model of epilepsy. T-type channel gene expression was not affected during SE; however Ca_V3.2 mRNA was significantly upregulated at both 10 d post-SE (seizure-free period) and 31 d post-SE (SRS-period). Overall T-type current density increased during the SRS period, and the steady-state inactivation shifted from a more hyperpolarized membrane potential during the latent stage, to a more depolarized membrane potential during the SRS period. Ca_V3.2 functional involvement was verified with Ca_V3.2 inhibitors that reduced the native T-type current in mice 31 d post-SE, but not in controls. Burst discharges of thalamic neurons reflected the changes in whole-cell currents, and we used a computational model to relate changes observed during epileptogenesis to a decreased tendency to burst in the seizure-free period, or an increased tendency to burst during the period of SRS. We conclude that SE produces an acquired channelopathy by inducing long-term alterations in thalamic T-type channels that contribute to characteristic changes in excitability observed during epileptogenesis and SRS.

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Received Jan. 13, 2009; revised Feb. 14, 2009; accepted Feb. 17, 2009.

Correspondence should be addressed to Dr. Dwayne W. Godwin, Department of Neurobiology and Anatomy, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27127. Email: dgodwin{at}wfubmc.edu

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