Binding of NRSF to the HCN1 Gene Represses Expression after Seizures

Abstract

Epilepsy is a devastating disorder that affects millions of people worldwide. One of the most common types of epilepsy, temporal lobe epilepsy (TLE), is associated with significant morbidity in cognitive and psychosocial dysfunction. TLE has long been correlated with a history of prolonged febrile seizures in childhood; hence, understanding the consequences of prolonged febrile seizures on TLE is of considerable clinical significance. The Baram Laboratory has consistently observed down-regulation after seizures of the hyperpolarization-activated cyclicnucleotide gated 1 (HCN1) channels that are responsible for mediating hyperpolarizationactivated (Ih) currents. In the hippocampus, these currents regulate the resting membrane potential, shape rhythmic and synchronized neuronal activity, and regulate the temporal summation of dendritic depolarization. This study targets the factors responsible for regulating the transcription of the HCN1 gene. By using chromatin immunoprecipitation (ChIP), polymerase chain reaction (PCR), and DNA electrophoresis, we show that the neuron restrictive silencer factor (NRSF) binds to the NRSE region in the first intron of the HCN1 gene. NRSF, in conjunction with its cofactors, deacetylates and methylates the chromatin, preventing transcription of the HCN1 gene. Such biochemical change may produce neuronal injury to the developing brain, promoting the onset of epilepsy.