C03 Mechanisms of zinc-sensitive metal-regulatory transcription factor 1 induction of hippocampal epileptic network activity
The emergence of a hyperexcitable hippocampal network is the pathogenetic hallmark of temporal lobe epilepsy (TLE), the most common focal epilepsy in adults. TLE generally develops after a transient brain insult via a multifaceted process referred to as epileptogenesis. Recent experimental and clinical evidence suggests that acquired ‘transcriptional channelopathies’ play a key role in epileptogenesis. In rodents, pilocarpine-induced status epilepticus causes a marked increase in the propensity for intrinsic bursting in hippocampal CA1 pyramidal cells (PCs) that is accompanied by a significant upregulation of CaV3.2 mRNA and protein levels as well as a 3-fold upregulation of the T-Type current. Interestingly, CaV3.2 deficient mice do not exhibit these intrinsic changes in CA1 PCs, and show reduced chronic seizure activity and attenuated hippocampal damage. Previously, we have determined a key transcriptional control mechanism of this ‘Cav3.2 channelopathy’ relying on the transient activity of a single transcription factor that can induce sustained hippocampal micronetwork plasticity. This metal-regulatory transcription factor 1 (MTF1) mediates the increase of CaV3.2 mRNA and intrinsic excitability, consequent to a rise in intracellular Zn2+. So far, the knowledge about comprehensive MTF1-induced signaling cascades and their functional relevance in neuronal circuits is very limited. Therefore, our overall goal will be to analyze in detail the molecular and functional network recruited by Zn2+-sensitive MTF1-signaling in a critical subset of hippocampal neurons that are capable to alter neuronal circuit activity.