Blockade of T-type calcium channels prevents tonic-clonic seizures in a maximal electroshock seizure model

• Maximal electroshock seizure (MES) was used to model tonic-clonic generalized seizures in mice.
• Mice treated with the T-type calcium channel inhibitor TTA-A2 develop less tonic seizures in the MES model.
• The ability of TTA-A2 treatment to protect from tonic seizures was reduced in Cav3.1−/− mice.

T-type (Cav3) calcium channels play important roles in neuronal excitability, both in normal and pathological activities of the brain. In particular, they contribute to hyper-excitability disorders such as epilepsy. Here we have characterized the anticonvulsant properties of TTA-A2, a selective T-type channel blocker, in mouse. Using the maximal electroshock seizure (MES) as a model of tonic-clonic generalized seizures, we report that mice treated with TTA-A2 (0.3 mg/kg and higher doses) were significantly protected against tonic seizures. Although no major change in Local Field Potential (LFP) pattern was observed during the MES seizure, analysis of the late post-ictal period revealed a significant increase in the delta frequency power in animals treated with TTA-A2. Similar results were obtained for Cav3.1−/− mice, which were less prone to develop tonic seizures in the MES test, but not for Cav3.2−/− mice. Analysis of extracellular signal-regulated kinase 1/2 (ERK) phosphorylation and c-Fos expression revealed a rapid and elevated neuronal activation in the hippocampus following MES clonic seizures, which was unchanged in TTA-A2 treated animals. Overall, our data indicate that TTA-A2 is a potent anticonvulsant and that the Cav3.1 isoform plays a prominent role in mediating TTA-A2 tonic seizure protection.