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Role of T-type calcium channels in the genesis of absence seizure in the mutant mice for alpha1A, the pore-forming subunit of the P/Q-type calcium channel

Role of T-type calcium channels in the genesis of absence seizure in the mutant mice for alpha1A, the pore-forming subunit of the P/Q-type calcium channel

Society for Neuroscience Abstracts 27(1): 397

We have previously shown that the knockout mice for the alpha1A subunit of the P/Q-type voltage-dependent calcium channel (CCalpha1A-/-) develop severe ataxia and dystonia (PNAS 96:15245,1999). In subsequent analysis, we have found that the CCalpha1A-/- mice also experience absence seizure, which is characterized by the appearance of 4-5 Hz spike-and-wave discharges in the electroencephalography recording. To gain insight into the cellular mechanisms underlying the absence seizure of CCalpha1A-/-, we examined voltage-dependent calcium currents in the thalamic relay neurons. Whole-cell patch clamp analysis done on acutely isolated neurons showed that the T-type calcium currents increased in the mutant cells (275.5+-45 pA for the mutant and 167.3+-21 pA for the wild: p<0.05) whereas high-voltage activated currents decreased in the mutant (149.8+-36 pA for the mutant and 312.3+-20 pA for the wild: p<0.001). To examine whether the increase of T-currents in the relay neurons is responsible for the genesis of SWDs in CCalpha1A-/- mice, we produced double mutant mice, CCalpha1A-/-/CCalpha1G-/-, by mating CCalpha1A+/- mice to CCalpha1G+/- mice, knockout mice for the alpha1G subunit of T-type channels. Interestingly, the SWDs disappeared in the double mutant mice, indicating that the CCalpha1G mutation suppressed the SWDs phenotype of CCalpha1A-/-. We conclude that alterations of the profile of voltage-dependent calcium currents, especially an increase of T-currents, could lead to the pathological synchronizing condition in the thalamocortical network, resulting in clinical absence epilepsy in vivo.

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