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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.

SUBMITTER: van Loo KM

PROVIDER: S-EPMC4846312 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

van Loo Karen M J KM Schaub Christina C Pitsch Julika J Kulbida Rebecca R Opitz Thoralf T Ekstein Dana D Dalal Adam A Urbach Horst H Beck Heinz H Yaari Yoel Y Schoch Susanne S Becker Albert J AJ

Nature communications 20151026

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 th ...[more]

PMID: 26498180

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

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

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