Voltage-gated calcium channels are key components in the etiology and pathogenesis of epilepsies. Former studies mainly focused on P/Q-type Ca(v)2.1 and T-type Ca(v)3.2 Ca(2+) channels involved in absence epileptogenesis, but recent findings also point to an intriguing role of the Ca(v)2.3 E/R-type Ca(2+) channel in ictogenesis and seizure propagation. Based on the observation that Ca(v)2.3 is thought to induce plateau potentials in CA1 pyramidal cells, which can trigger epileptiform activity, our recent investigation revealed reduced PTZ-seizure susceptibility and altered seizure architecture in Ca(v)2.3(-/-) mice compared with controls. In the present study we tested hippocampal seizure susceptibility in Ca(v)2.3-deficient mice using surface and deep intrahippocampal telemetric EEG recordings as well as phenotypic seizure video analysis. Administration of kainic acid (30 mg/kg ip) revealed clear alteration in behavioral seizure architecture and dramatic resistance to limbic seizures in Ca(v)2.3(-/-) mice compared with controls, whereas no difference in hippocampal EEG seizure activity between both genotypes could be detected at this suprathreshold dosage. The same tendency was observed for NMDA seizure susceptibility (150 mg/kg ip) approaching the level of significance. In addition, histochemical analysis within the hippocampus revealed that excitotoxic effects after kainic acid administration are absent in Ca(v)2.3(-/-) mice, whereas Ca(v)2.3(+/+) animals exhibited clear and typical signs of excitotoxic cell death. These findings clearly indicate that the Ca(v)2.3 voltage-gated calcium channel plays a crucial role in both hippocampal ictogenesis and seizure generalization and is of central importance in neuronal degeneration after excitotoxic events.