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 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.

journal_name

Nat Commun

journal_title

Nature communications

authors

van Loo KM,Schaub C,Pitsch J,Kulbida R,Opitz T,Ekstein D,Dalal A,Urbach H,Beck H,Yaari Y,Schoch S,Becker AJ

doi

10.1038/ncomms9688

subject

Has Abstract

pub_date

2015-10-26 00:00:00

pages

8688

issn

2041-1723

pii

ncomms9688

journal_volume

6

pub_type

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