Temporal lobe epilepsy (TLE) is a common and severe, often therapy-refractory seizure disorder. The underlying mechanisms during its etiopathogenesis, referred to as epileptogenesis, are however poorly understood. Recently, we have discovered that transcriptional activation of the T-type Ca2+ channel subunit CaV3.2 plays a critical role in the pilocarpine-SE model of epileptogenesis, an animal model that mimics the acquirement of TLE in humans. Within 2-3 days after SE, a transcriptional upregulation of CaV3.2 in the CA1 of the hippocampus was observed. The rise in CaV3.2 expression levels was accompanied by a 3-fold increase of T-type calcium currents and an increased propensity to a burst firing-mode. CaV3.2 knockout (CaV3.2-/-) mice after pilocarpine-induced SE, lack this cascade and show attenuated chronic seizure activity and hippocampal damage. Unfortunately, specific pharmacological blockers for CaV3.2 are not available yet. This aspect stresses the importance to understand in detail transcriptional control mechanisms of CaV3.2 in order to potentially interfere with the upregulation of the channel after SE.
Our main focus is to identify the molecular signaling cascades involved in CaV3.2 transcriptional regulation. To this end, we use cell-based assays to identify the transcriptional cascades involved in CaV3.2 regulation. In addition, we use the pilocarpine model of epileptogenesis, combined with adeno-associated viral (AAVs) approaches to analyze the signaling cascades in vivo. By applying such a combination of molecular, biochemical and behavioral experiments, we expect to improve our understanding of the CaV3.2 transcriptional mechanisms in epileptogenesis, which can be used to develop new strategies for pharmacological intervention in TLE pathogenesis, including the design of gene/pathway-specific drugs..