Neuron-restrictive silencer factor-mediated hyperpolarization-activated cyclic nucleotide gated channelopathy in experimental temporal lobe epilepsy

Shawn McClelland, Corey Flynn, Celine Dubé, Cristina Richichi, Qinqin Zha, Antoine Ghestem, Monique Esclapez, Christophe Bernard, Tallie Z. Baram

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

Objective: Enduring, abnormal expression and function of the ion channel hyperpolarization-activated cyclic adenosine monophosphate gated channel type 1 (HCN1) occurs in temporal lobe epilepsy (TLE). We examined the underlying mechanisms, and investigated whether interfering with these mechanisms could modify disease course. Methods: Experimental TLE was provoked by kainic acid-induced status epilepticus (SE). HCN1 channel repression was examined at mRNA, protein, and functional levels. Chromatin immunoprecipitation was employed to identify the transcriptional mechanism of repressed HCN1 expression, and the basis for their endurance. Physical interaction of the repressor, NRSF, was abolished using decoy oligodeoxynucleotides (ODNs). Video/ electroencephalographic recordings were performed to assess the onset and initial pattern of spontaneous seizures. Results: Levels of NRSF and its physical binding to the Hcn1 gene were augmented after SE, resulting in repression of HCN1 expression and HCN1-mediated currents (Ih), and reduced Ih-dependent resonance in hippocampal CA1 pyramidal cell dendrites. Chromatin changes typical of enduring, epigenetic gene repression were apparent at the Hcn1 gene within a week after SE. Administration of decoy ODNs comprising the NRSF DNA-binding sequence (neuron restrictive silencer element [NRSE]), in vitro and in vivo, reduced NRSF binding to Hcn1, prevented its repression, and restored Ih function. In vivo, decoy NRSE ODN treatment restored theta rhythm and altered the initial pattern of spontaneous seizures. Interpretation: Acquired HCN1 channelopathy derives from NRSF-mediated transcriptional repression that endures via chromatin modification and may provide insight into the mechanisms of a number of channelopathies that coexist with, and may contribute to, the conversion of a normal brain into an epileptic one.

Original languageEnglish
Pages (from-to)454-464
Number of pages11
JournalAnnals of Neurology
Volume70
Issue number3
DOIs
Publication statusPublished - Sep 2011

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Channelopathies
Temporal Lobe Epilepsy
Status Epilepticus
Oligodeoxyribonucleotides
Cyclic Nucleotides
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
Transcriptional Silencer Elements
Chromatin
Epigenetic Repression
Seizures
Theta Rhythm
Genes
Neurons
Video Recording
Pyramidal Cells
Chromatin Immunoprecipitation
Kainic Acid
Dendrites
Ion Channels
Cyclic AMP

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Neuron-restrictive silencer factor-mediated hyperpolarization-activated cyclic nucleotide gated channelopathy in experimental temporal lobe epilepsy. / McClelland, Shawn; Flynn, Corey; Dubé, Celine; Richichi, Cristina; Zha, Qinqin; Ghestem, Antoine; Esclapez, Monique; Bernard, Christophe; Baram, Tallie Z.

In: Annals of Neurology, Vol. 70, No. 3, 09.2011, p. 454-464.

Research output: Contribution to journalArticle

McClelland, Shawn ; Flynn, Corey ; Dubé, Celine ; Richichi, Cristina ; Zha, Qinqin ; Ghestem, Antoine ; Esclapez, Monique ; Bernard, Christophe ; Baram, Tallie Z. / Neuron-restrictive silencer factor-mediated hyperpolarization-activated cyclic nucleotide gated channelopathy in experimental temporal lobe epilepsy. In: Annals of Neurology. 2011 ; Vol. 70, No. 3. pp. 454-464.
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AU - Flynn, Corey

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AU - Richichi, Cristina

AU - Zha, Qinqin

AU - Ghestem, Antoine

AU - Esclapez, Monique

AU - Bernard, Christophe

AU - Baram, Tallie Z.

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