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The Journal of Neuroscience, June 2, 2004, 24(22):5249-5257; doi:10.1523/JNEUROSCI.5546-03.2004

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Neurobiology of Disease
Role of the 1G T-Type Calcium Channel in Spontaneous Absence Seizures in Mutant Mice

Inseon Song,^1,2 Daesoo Kim,¹ Soonwook Choi,¹ Minjeong Sun,^1,2 Yeongin Kim,³ and Hee-Sup Shin¹

¹Center for Calcium and Learning, Korea Institute of Science and Technology, Cheongryang, Seoul, 136-791, Korea, ²Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, 790-784, Korea, and ³Department of Neurology, Kangnam St. Mary's Hospital, Catholic University of Korea, Seocho-gu, Seoul, 137-701, Korea

Alterations in thalamic T-type Ca²⁺ channels are thought to contribute to the pathogenesis of absence seizures. Here, we found that mice with a null mutation for the pore-forming 1A subunits of P/Q-type channels (1A^–/– mice) were prone to absence seizures characterized by typical spike-and-wave discharges (SWDs) and behavioral arrests. Isolated thalamocortical relay (TC) neurons from these mice showed increased T-type Ca²⁺ currents in vitro. To examine the role of increased T-currents in 1A^–/– TC neurons, we cross-bred 1A^–/– mice with mice harboring a null mutation for the gene encoding 1G, a major isotype of T-type Ca²⁺ channels in TC neurons. 1A^–/–/1G^–/– mice showed a complete loss of T-type Ca²⁺ currents in TC neurons and displayed no SWDs. Interestingly, 1A^–/–/1G^+/– mice had 75% of the T-type Ca²⁺ currents in TC neurons observed in 1A^+/+/1G^+/+ mice and showed SWD activity that was quantitatively similar to that in 1A^–/–/1G^+/+ mice. Similar results were obtained using double-mutant mice harboring the 1G mutation plus another mutation also used as a model for absence seizures, i.e., lethargic (4^lh/lh), tottering (1A^tg/tg), or stargazer (2^stg/stg). The present results reveal that 1G T-type Ca²⁺ channels play a critical role in the genesis of spontaneous absence seizures resulting from hypofunctioning P/Q-type channels, but that the augmentation of thalamic T-type Ca²⁺ currents is not an essential step in the genesis of absence seizures.

Key words: calcium; Ca; EEG; electroencephalogram; epilepsy; gene; mutant; thalamus

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Received Dec 17, 2003; revised April 21, 2004; accepted April 22, 2004.

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