title: Rapid loss of dendritic HCN channel expression in hippocampal pyramidal neurons following status epilepticus.
abstract: Epilepsy is associated with loss of expression and function of hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels. Previously, we showed that loss of HCN channel-mediated current (I(h)) occurred in the dendrites of CA1 hippocampal pyramidal neurons after pilocarpine-induced status epilepticus (SE), accompanied by loss of HCN1 channel protein expression. However, the precise onset and mechanistic basis of HCN1 channel loss post-SE was unclear, particularly whether it preceded the onset of spontaneous recurrent seizures and could contribute to epileptogenesis or development of the epileptic state. Here, we found that loss of I(h) and HCN1 channel expression began within an hour after SE and involved sequential processes of dendritic HCN1 channel internalization, delayed loss of protein expression, and later downregulation of mRNA expression. We also found that an in vitro SE model reproduced the rapid loss of dendritic I(h), demonstrating that this phenomenon was not specific to in vivo SE. Together, these results show that HCN1 channelopathy begins rapidly and persists after SE, involves both transcriptional and nontranscriptional mechanisms, and may be an early contributor to epileptogenesis.
authors: Department of Neurology and Regional Epilepsy Center, University of Washington, Seattle, Washington 98104, USA.
authors: Sangwook
authors: S
authors: Jung
authors: Lindsay N
authors: LN
authors: Warner
authors: Julika
authors: J
authors: Pitsch
authors: Albert J
authors: AJ
authors: Becker
authors: Nicholas P
authors: NP
authors: Poolos
mesh_terms: D000818:Animals; D002452:Cell Count / Q000379:methods; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology*; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D008297:Male; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D013997:Time Factors
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; C578667:Hcn1 protein, rat; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015221:Potassium Channels