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Zinc regulates a key transcriptional pathway for epileptogenesis via metal-regulatory transcription factor 1
- Source :
- Nature Communications
- Publication Year :
- 2015
- Publisher :
- Springer Science and Business Media LLC, 2015.
-
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 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.<br />Temporal lobe epilepsy can cause ionic imbalance in the brain and alter transcriptional activities. Here, van Loo et al. show that the increase in neuronal zinc following status epilepticus can induce transcriptional change via metal-regulatory transcription factor 1, and alter voltage-gated calcium channel CaV3.2 and intrinsic neuronal excitability.
- Subjects :
- Male
General Physics and Astronomy
Status epilepticus
Hippocampal formation
Biology
Epileptogenesis
Article
General Biochemistry, Genetics and Molecular Biology
Metal regulatory transcription factor 1
Calcium Channels, T-Type
Mice
Epilepsy
Status Epilepticus
Downregulation and upregulation
medicine
Animals
Humans
Transcription factor
Regulation of gene expression
Multidisciplinary
General Chemistry
medicine.disease
Rats
Cell biology
DNA-Binding Proteins
Mice, Inbred C57BL
Zinc
Epilepsy, Temporal Lobe
Gene Expression Regulation
medicine.symptom
Transcription Factors
Subjects
Details
- ISSN :
- 20411723
- Volume :
- 6
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....2ea5e3e526937f00b4f59b770ce23e7b