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

Karen M J Van Loo,Yoel Yaari,Horst Urbach,Dana Ekstein,Thoralf Opitz,Susanne Schoch,Rebecca Kulbida,Albert J Becker,Julika Pitsch,Heinz Beck,Christina Schaub,Adam Dalal

doi:10.1038/ncomms9688

Karen M J Van Loo, Yoel Yaari + Show 10 more

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https://doi.org/10.1038/ncomms9688

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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.

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Temporal lobe epilepsy (TLE) is the most common focal seizure disorder in adults
Zn2 þ –metal-regulatory transcription factor 1 (MTF1)–CaV3.2 cascade, wherein a rise in MTF1, which binds to MREs in the CaV3.2 gene promoter and increases transcription of this gene
PilocarpineSE leads to a rise in [Zn2 þ ]i in CA1 pyramidal cells, appearing within a day and persisting for at least 1 week

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Introduction

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. Transcriptional upregulation of CaV3.2 T-type Ca2 þ -channels, resulting in an increased propensity for burst discharges of hippocampal neurons, is an important trigger for epileptogenesis. 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 þ that is associated with SE. Adeno-associated viral (rAAV) transfer of MTF1 into murine hippocampi leads to increased CaV3.2 mRNA. RAAV-mediated expression of a dominant-negative MTF1 abolishes SE-induced CaV3.2 mRNA upregulation and attenuates epileptogenesis. In rodents, SE induced chemically with pilocarpine (pilocarpine-SE) causes a marked increase in the propensity for intrinsic bursting in hippocampal CA1 pyramidal cells, in the early phase of epileptogenesis[10]. CaV3.2 mRNA, but not that a1 mRNAs, was present in of other T-type SE-experienced neurons and translated to an increase in CaV3.2 protein level[13]

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