Role of the alpha1G T-type calcium channel in spontaneous absence seizures in mutant mice.
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 alpha1A subunits of P/Q-type channels (alpha1A-/- 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 alpha1A-/- TC neurons, we cross-bred alpha1A-/- mice with mice harboring a null mutation for the gene encoding alpha1G, a major isotype of T-type Ca2+ channels in TC neurons. alpha1A-/-/alpha1G-/- mice showed a complete loss of T-type Ca2+ currents in TC neurons and displayed no SWDs. Interestingly, alpha1A-/-/alpha1G+/- mice had 75% of the T-type Ca2+ currents in TC neurons observed in alpha1A+/+/alpha1G+/+ mice and showed SWD activity that was quantitatively similar to that in alpha1A-/-/alpha1G+/+ mice. Similar results were obtained using double-mutant mice harboring the alpha1G mutation plus another mutation also used as a model for absence seizures, i.e., lethargic (beta4(lh/lh)), tottering (alpha1A(tg/tg)), or stargazer (gamma2(stg/stg)). The present results reveal that alpha1G 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.
Song
Inseon
I
Center for Calcium and Learning, Korea Institute of Science and Technology, Cheongryang, Seoul, 136-791, Korea.
Kim
Daesoo
D
Choi
Soonwook
S
Sun
Minjeong
M
Kim
Yeongin
Y
Shin
Hee-Sup
HS
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020864:Calcium Channels, N-Type / Q000172:deficiency / Q000235:genetics; D020747:Calcium Channels, T-Type / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D002469:Cell Separation; D002540:Cerebral Cortex / Q000503:physiopathology; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D018450:Disease Progression; D004567:Electrodes, Implanted; D004569:Electroencephalography; D004832:Epilepsy, Absence / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008818:Mice, Neurologic Mutants; D009154:Mutation; D009434:Neural Pathways / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism; D018408:Patch-Clamp Techniques; D021122:Protein Subunits / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013788:Thalamus / Q000503:physiopathology
D002118:Calcium; D020864:Calcium Channels, N-Type; D020747:Calcium Channels, T-Type; D021122:Protein Subunits