Zinc regulates a key transcriptional pathway for epileptogenesis via metal-regulatory transcription factor 1.
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 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 CaV3.2 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 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 Zn(2+)-MTF1-CaV3.2 cascade, thus providing new vistas for preventing and treating TLE.
Section for Translational Epilepsy Research, Department of Neuropathology, University of Bonn Medical Center, Bonn 53105, Germany.
Karen M J
KM
van Loo
Laboratory for Experimental Epileptology and Cognition Research, Department of Epileptology, University of Bonn Medical Center, Bonn 53105, Germany.|Department of Neurology, University of Bonn Medical Center, Bonn 53105, Germany.
Christina
C
Schaub
Section for Translational Epilepsy Research, Department of Neuropathology, University of Bonn Medical Center, Bonn 53105, Germany.
Julika
J
Pitsch
Section for Translational Epilepsy Research, Department of Neuropathology, University of Bonn Medical Center, Bonn 53105, Germany.
Rebecca
R
Kulbida
Laboratory for Experimental Epileptology and Cognition Research, Department of Epileptology, University of Bonn Medical Center, Bonn 53105, Germany.
Thoralf
T
Opitz
Department of Medical Neurobiology, IMRIC, Hebrew University-Hadassah School of Medicine, Jerusalem 91120, Israel.|Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
Dana
D
Ekstein
Department of Medical Neurobiology, IMRIC, Hebrew University-Hadassah School of Medicine, Jerusalem 91120, Israel.
Adam
A
Dalal
Department of Neuroradiology, Medical Center University of Freiburg, Freiburg 79106, Germany.
Horst
H
Urbach
Laboratory for Experimental Epileptology and Cognition Research, Department of Epileptology, University of Bonn Medical Center, Bonn 53105, Germany.
Heinz
H
Beck
Department of Medical Neurobiology, IMRIC, Hebrew University-Hadassah School of Medicine, Jerusalem 91120, Israel.
Yoel
Y
Yaari
Section for Translational Epilepsy Research, Department of Neuropathology, University of Bonn Medical Center, Bonn 53105, Germany.
Susanne
S
Schoch
Section for Translational Epilepsy Research, Department of Neuropathology, University of Bonn Medical Center, Bonn 53105, Germany.
Albert J
AJ
Becker
D000818:Animals; D020747:Calcium Channels, T-Type / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004833:Epilepsy, Temporal Lobe / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D013226:Status Epilepticus / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism*; D000097809:Transcription Factor MTF-1
D020747:Calcium Channels, T-Type; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D015032:Zinc; D000097809:Transcription Factor MTF-1; C504883:Cacna1h protein, mouse