Role of the α1G T-type calcium channel in spontaneous absence seizures in mutant mice

Abstract

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 α1A subunits of P/Q-type channels (α1A-/- 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 α1A-/- TC neurons, we cross-bred α1A-/- mice with mice harboring a null mutation for the gene encoding α1G, a major isotype of T-type Ca2+ channels in TC neurons. α1A-/-/α1G-/- mice showed a complete loss of T-type Ca2+ currents in TC neurons and displayed no SWDs. Interestingly, α1A-/-/α1G+/- mice had 75% of the T-type Ca2+ currents in TC neurons observed in α1A +/+/α1G+/+ mice and showed SWD activity that was quantitatively similar to that in α1A-/-/α1G +/+ mice. Similar results were obtained using double-mutant mice harboring the α1G mutation plus another mutation also used as a model for absence seizures, i.e., lethargic (β4lh/lh), tottering (α1Atg/tg), or stargazer (γ2stg/stg). The present results reveal that α1G 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.