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

Author

Listed:
  • 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
    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
    Hadassah—Hebrew University Medical Center)

  • 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)

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.

Suggested Citation

  • 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 & Albert J. Becker, 2015. "Zinc regulates a key transcriptional pathway for epileptogenesis via metal-regulatory transcription factor 1," Nature Communications, Nature, vol. 6(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9688
    DOI: 10.1038/ncomms9688
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