Abstracts

Mutations in several high-voltage-activated (HVA) calcium channel subunits are associated with absence epilepsy in mouse models. Recent studies suggest these mutations initiate downstream enhancement of low-voltage-activated (LVA) T-type currents that increases membrane excitability in thalamic neurons and leads to rhythmic thalamocortical burst firing and spike-wave seizures., To determine whether elevation of T-type currents, in the absence of HVA calcium channel mutations, is alone sufficient to produce an epileptic phenotype, we generated transgenic mice by pronuclear microinjection of a BAC clone containing the [italic]Cacna1g[/italic] gene encoding the T-type calcium channel, [alpha][sub]1G [/sub](Ca[sub]v[/sub]3.1), under control of its endogenous promoter., Two transgenic lines were obtained integrating low and high transgene copy numbers, as determined by quantitative PCR analysis of genomic DNA. Corresponding increases in [italic]Cacna1g[/italic] mRNA expression levels within the brain were observed by quantitative RT-PCR using an [alpha][sub]1G[/sub]-specific primer and probe set. Both transgenic mouse lines appear phenotypically normal with no overt behavioral or neuromuscular abnormalities. EEG monitoring of each [alpha][sub]1G [/sub]transgenic line showed frequent generalized interictal-like cortical spike-wave discharges, and occasional rhythmic discharges., These transgenic lines provide the first evidence that primary elevations of [alpha][sub]1G [/sub]T-type channels are sufficient to induce patterns of hypersynchronous oscillations in the brain and represent new mouse models to explore the basis of spike-wave epilepsy., (Supported by: This research is funded by NINDS Grant 29709 (JLN).)