Mechanisms of seizure-induced 'transcriptional channelopathy' of hyperpolarization-activated cyclic nucleotide gated (HCN) channels

Cristina Richichi, Amy L. Brewster, Roland A. Bender, Timothy Simeone, Qinqin Zha, Hong Z. Yin, John H. Weiss, Tallie Z. Baram

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63 Citations (Scopus)

Abstract

Epilepsy may result from abnormal function of ion channels, such as those caused by genetic mutations. Recently, pathological alterations of the expression or localization of normal channels have been implicated in epilepsy generation, and termed 'acquired channelopathies'. Altered expression levels of the HCN channels - that conduct the hyperpolarization-activated current, Ih - have been demonstrated in hippocampus of patients with severe temporal lobe epilepsy as well as in animal models of temporal lobe and absence epilepsies. Here we probe the mechanisms for the altered expression of HCN channels which is provoked by seizures. In organotypic hippocampal slice cultures, seizure-like events selectively reduced HCN type 1 channel expression and increased HCN2 mRNA levels, as occurs in vivo. The mechanisms for HCN1 reduction involved Ca2+-permeable AMPA receptor-mediated Ca2+ influx, and subsequent activation of Ca2+/calmodulin-dependent protein kinase II. In contrast, upregulation of HCN2 expression was independent of these processes. The data demonstrate an orchestrated program for seizure-evoked transcriptional channelopathy involving the HCN channels that may contribute to certain epilepsies.

Original languageEnglish
Pages (from-to)297-305
Number of pages9
JournalNeurobiology of Disease
Volume29
Issue number2
DOIs
StatePublished - Feb 2008

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Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
Channelopathies
Seizures
Epilepsy
Temporal Lobe Epilepsy
Absence Epilepsy
Calcium-Calmodulin-Dependent Protein Kinase Type 2
AMPA Receptors
Ion Channels
Hippocampus
Up-Regulation
Animal Models
Messenger RNA
Mutation

All Science Journal Classification (ASJC) codes

  • Neurology

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Mechanisms of seizure-induced 'transcriptional channelopathy' of hyperpolarization-activated cyclic nucleotide gated (HCN) channels. / Richichi, Cristina; Brewster, Amy L.; Bender, Roland A.; Simeone, Timothy; Zha, Qinqin; Yin, Hong Z.; Weiss, John H.; Baram, Tallie Z.

In: Neurobiology of Disease, Vol. 29, No. 2, 02.2008, p. 297-305.

Research output: Contribution to journalArticle

Richichi, Cristina ; Brewster, Amy L. ; Bender, Roland A. ; Simeone, Timothy ; Zha, Qinqin ; Yin, Hong Z. ; Weiss, John H. ; Baram, Tallie Z. / Mechanisms of seizure-induced 'transcriptional channelopathy' of hyperpolarization-activated cyclic nucleotide gated (HCN) channels. In: Neurobiology of Disease. 2008 ; Vol. 29, No. 2. pp. 297-305.
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