title: Neuron-restrictive silencer factor-mediated hyperpolarization-activated cyclic nucleotide gated channelopathy in experimental temporal lobe epilepsy.
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 (I(h) ), and reduced I(h) -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 I(h) function. In vivo, decoy NRSE ODN treatment restored theta rhythm and altered the initial pattern of spontaneous seizures.
  
  
  CONCLUSIONS
  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.
authors: Departments of Anatomy/Neurobiology, Pediatrics, and Neurology, University of California-Irvine, Irvine, CA, USA.
authors: Shawn
authors: S
authors: McClelland
authors: Corey
authors: C
authors: Flynn
authors: Celine
authors: C
authors: Dubé
authors: Cristina
authors: C
authors: Richichi
authors: Qinqin
authors: Q
authors: Zha
authors: Antoine
authors: A
authors: Ghestem
authors: Monique
authors: M
authors: Esclapez
authors: Christophe
authors: C
authors: Bernard
authors: Tallie Z
authors: TZ
authors: Baram
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000473:pathology; D053447:Channelopathies / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D002843:Chromatin / Q000473:pathology; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics / Q000502:physiology*; D003712:Dendrites / Q000473:pathology; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D018690:Excitatory Amino Acid Agonists; D015870:Gene Expression / Q000235:genetics / Q000502:physiology; D006624:Hippocampus / Q000473:pathology; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015640:Ion Channel Gating / Q000502:physiology; D007608:Kainic Acid; D008297:Male; D009712:Nucleotides, Cyclic / Q000378:metabolism*; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D013226:Status Epilepticus / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D000099229:RE1-Silencing Transcription Factor
chemical_list: D002843:Chromatin; D054815:Cyclic Nucleotide-Gated Cation Channels; D018690:Excitatory Amino Acid Agonists; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007608:Kainic Acid; D009712:Nucleotides, Cyclic; D015221:Potassium Channels; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C578667:Hcn1 protein, rat