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

Karen M. J. van Loo, Christina Schaub, Julika Pitsch, Rebecca Kulbida, Thoralf Opitz, Dana Ekstein, Adam Dalal, Horst Urbach, Heinz Beck, Yoel Yaari, Susanne Schoch and Albert J. Becker ()
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Karen M. J. van Loo: Section for Translational Epilepsy Research, University of Bonn Medical Center
Christina Schaub: Laboratory for Experimental Epileptology and Cognition Research, University of Bonn Medical Center
Julika Pitsch: Section for Translational Epilepsy Research, University of Bonn Medical Center
Rebecca Kulbida: Section for Translational Epilepsy Research, University of Bonn Medical Center
Thoralf Opitz: Laboratory for Experimental Epileptology and Cognition Research, University of Bonn Medical Center
Dana Ekstein: IMRIC, Hebrew University–Hadassah School of Medicine
Adam Dalal: IMRIC, Hebrew University–Hadassah School of Medicine
Horst Urbach: Medical Center University of Freiburg
Heinz Beck: Laboratory for Experimental Epileptology and Cognition Research, University of Bonn Medical Center
Yoel Yaari: IMRIC, Hebrew University–Hadassah School of Medicine
Susanne Schoch: Section for Translational Epilepsy Research, University of Bonn Medical Center
Albert J. Becker: Section for Translational Epilepsy Research, University of Bonn Medical Center

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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 CaV3.2 T-type Ca2+-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 CaV3.2 mRNA and intrinsic excitability consequent to a rise in intracellular Zn2+ that is associated with SE. Adeno-associated viral (rAAV) transfer of MTF1 into murine hippocampi leads to increased CaV3.2 mRNA. Conversely, rAAV-mediated expression of a dominant-negative MTF1 abolishes SE-induced CaV3.2 mRNA upregulation and attenuates epileptogenesis. Finally, data from resected human hippocampi surgically treated for pharmacoresistant TLE support the Zn2+-MTF1-CaV3.2 cascade, thus providing new vistas for preventing and treating TLE.

Date: 2015
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DOI: 10.1038/ncomms9688

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