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The Journal of Neuroscience, February 11, 2009, 29(6):1615-1625; doi:10.1523/JNEUROSCI.2081-08.2009

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Neurobiology of Disease
Genetic Enhancement of Thalamocortical Network Activity by Elevating 1G-Mediated Low-Voltage-Activated Calcium Current Induces Pure Absence Epilepsy

Wayne L. Ernst,^1,2 Yi Zhang,^1,3 * Jong W. Yoo,^1,3 * Sara J. Ernst,^1,2 and Jeffrey L. Noebels^1,2,3,4

¹Developmental Neurogenetics Laboratory and Departments of ²Molecular and Human Genetics, ³Neurology, and ⁴Neuroscience, Baylor College of Medicine, Houston, Texas 77030

Correspondence should be addressed to Dr. Jeffrey L. Noebels, Department of Neurology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Email: jnoebels{at}bcm.tmc.edu

Absence seizures are a leading form of childhood epilepsy. Human and mouse P/Q-type calcium channel gene mutations initiate a complex absence epilepsy and ataxia phenotype, and in mice, secondarily elevate neuronal low-voltage-activated T-type calcium currents. These currents influence thalamocortical network activity and contribute to the generation of cortical spike-wave discharges (SWDs) associated with absence seizures. To address whether enhanced thalamocortical T-type currents suffice to induce an epileptic phenotype, two BAC transgenic mouse lines overexpressing the Cacna1g gene for 1G T-type calcium channels were generated with low and high transgene copy numbers that exhibit elevated 1G expression and showed increased functional T-type currents measured in thalamic neurons. Both lines exhibit frequent bilateral cortical SWDs associated with behavioral arrest but lack other overt neurological abnormalities. These models provide the first evidence that primary elevation of brain T-type currents are causally related to pure absence epilepsy, and selectively identify Cacna1g, one of the three T-type calcium channel genes, as a key component of a genetically complex epileptogenic pathway.

Key words: Bac transgenic; T-type calcium channel; mutant mouse; network; seizure; epilepsy

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Received May 6, 2008; revised Sept. 10, 2008; accepted Jan. 5, 2009.

Correspondence should be addressed to Dr. Jeffrey L. Noebels, Department of Neurology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Email: jnoebels{at}bcm.tmc.edu

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