Zinc regulates a key transcriptional pathway for epileptogenesis via metal-regulatory transcription factor 1

Abstract

Temporal lobe epilepsy (TLE) is the most common focal seizure disorder in adults. In many patients, transient brain insults, including status epilepticus (SE), are followed by a latent period of epileptogenesis, preceding the emergence of clinical seizures. In experimental animals, transcriptional upregulation of Ca V 3.2 T-type Ca 2+ -channels, resulting in an increased propensity for burst discharges of hippocampal neurons, is an important trigger for epileptogenesis. Here we provide evidence that the metal-regulatory transcription factor 1 (MTF1) mediates the increase of Ca V 3.2 mRNA and intrinsic excitability consequent to a rise in intracellular Zn 2+ that is associated with SE. Adeno-associated viral (rAAV) transfer of MTF1 into murine hippocampi leads to increased Ca V 3.2 mRNA. Conversely, rAAV-mediated expression of a dominant-negative MTF1 abolishes SE-induced Ca V 3.2 mRNA upregulation and attenuates epileptogenesis. Finally, data from resected human hippocampi surgically treated for pharmacoresistant TLE support the Zn 2+ -MTF1-Ca V 3.2 cascade, thus providing new vistas for preventing and treating TLE.