TY - JOUR
T1 - Zinc regulates a key transcriptional pathway for epileptogenesis via metal-regulatory transcription factor 1
AU - Van Loo, Karen M.J.
AU - Schaub, Christina
AU - Pitsch, Julika
AU - Kulbida, Rebecca
AU - Opitz, Thoralf
AU - Ekstein, Dana
AU - Dalal, Adam
AU - Urbach, Horst
AU - Beck, Heinz
AU - Yaari, Yoel
AU - Schoch, Susanne
AU - Becker, Albert J.
N1 - Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.
PY - 2015/10/26
Y1 - 2015/10/26
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84945391440&partnerID=8YFLogxK
U2 - 10.1038/ncomms9688
DO - 10.1038/ncomms9688
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C2 - 26498180
AN - SCOPUS:84945391440
SN - 2041-1723
VL - 6
JO - Nature Communications
JF - Nature Communications
M1 - 8688
ER -
