Voltage-gated calcium channels are key components in the etiopathogenesis of epilepsies and hippocampal Cav2.3 E/R-type voltage-gated Ca2+ channels may play an important role in ictogenesis and seizure propagation. Our recent investigation revealed reduced PTZ-seizure susceptibility and altered seizure architecture in Cav2.3-/- mice compared to controls. In the present study we tested hippocampal seizure susceptibility in Cav2.3 deficient mice using surface and deep intrahippocampal telemetric EEG recordings as well as phenotypic seizure video analysis. Administration of kainic acid (30 mg/kg i.p.) and NMDA (150 mg/kg i.p.) unmasked clear alteration in behavioral seizure architecture and dramatic resistance to limbic seizures in Cav2.3-/- mice compared to controls. In addition, histochemical analysis within the hippocampus revealed that excitotoxic effects following kainic acid administration are absent in Cav2.3-/- mice, whereas Cav2.3+/+ animals exhibited typical signs of excitotoxic cell death. These findings clearly indicate that the Cav2.3 voltage- gated calcium channel plays a crucial role in both hippocampal ictogenesis and seizure generalization and is of central importance in neuronal degeneration following excitotoxic events.