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

Ann Neurol. 2011 Sep;70(3):454-64. doi: 10.1002/ana.22479.


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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CA1 Region, Hippocampal / pathology
  • Channelopathies / genetics
  • Channelopathies / metabolism
  • Channelopathies / physiopathology*
  • Chromatin / pathology
  • Cyclic Nucleotide-Gated Cation Channels / genetics
  • Cyclic Nucleotide-Gated Cation Channels / physiology*
  • Dendrites / pathology
  • Epilepsy, Temporal Lobe / chemically induced
  • Epilepsy, Temporal Lobe / metabolism
  • Epilepsy, Temporal Lobe / physiopathology*
  • Excitatory Amino Acid Agonists
  • Gene Expression / genetics
  • Gene Expression / physiology
  • Hippocampus / pathology
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channel Gating / physiology
  • Kainic Acid
  • Male
  • Nucleotides, Cyclic / metabolism*
  • Potassium Channels / genetics
  • Potassium Channels / physiology*
  • Rats
  • Rats, Wistar
  • Repressor Proteins / antagonists & inhibitors
  • Repressor Proteins / physiology*
  • Status Epilepticus / chemically induced
  • Status Epilepticus / metabolism
  • Status Epilepticus / physiopathology


  • Chromatin
  • Cyclic Nucleotide-Gated Cation Channels
  • Excitatory Amino Acid Agonists
  • Hcn1 protein, rat
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Nucleotides, Cyclic
  • Potassium Channels
  • RE1-silencing transcription factor
  • Repressor Proteins
  • Kainic Acid