Abstracts

Rationale: Loss of function mutations in P/Q-type calcium channel alpha subunit (CACNA1A) gene lead to absence epilepsy with ataxia in humans and mouse models.  While P/Q-type calcium channels are broadly expressed throughout the central nervous system, they are most prominently expressed in two brain regions: cerebellar Purkinje cells and CA3 hippocampal neurons. It has been reported that conditional knockout of P/Q-type calcium channels in cerebellar Purkinje cells recapitulated genomic Cacna1a mutation phenotype of ataxia and spike-wave seizures in mice, while selective deletion of these channels from layer 6 cortical pyramidal cells produces absence seizures without ataxia. The potential contribution of hippocampal P/Q-type calcium channels to the generation of absence seizures, however, remains unclear. The extensive recurrent connectivity in the hippocampal CA3 region has long been hypothesized to be involved in the generation of aberrant oscillatory activities such as temporal lobe epilepsy in the brain. We therefore hypothesized that loss of P/Q-type calcium channels in hippocampal CA3 circuits might also play an important role in generating spike-wave seizure. Methods: To test this hypothesis, we selectively ablated Cacna1a in CA3 pyramidal cells by crossing a kainate receptor 4 (Grik4)-expressing cre line with Cacna1a floxed mice. Results: We first confirmed the specific expression of cre in pyramidal, but not GABAergic neurons using the Ai9 reporter line. Using video EEG monitoring, we found that these mutant mice developed typical generalized absence seizures accompanied by behavioral arrest near the end of the seventh postnatal week. The mice show no ataxia, As in the original tottering mice, these seizures could be reversibly blocked by ethosuximide. Conclusions: Our results provide direct evidence that early hippocampal signaling defects due to loss of CA3 P/Q-type calcium channels are sufficient to produce a phenotype of  absence epilepsy.  Funding: NINDS NS29709 (JLN)