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⁺currentsin 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(β4^lh/lh),tottering(α1A^tg/tg), orstargazer(γ2^stg/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.