title: Increased seizure severity and seizure-related death in mice lacking HCN1 channels.
abstract: Persistent down-regulation in the expression of the hyperpolarization-activated HCN1 cation channel, a key determinant of intrinsic neuronal excitability, has been observed in febrile seizure, temporal lobe epilepsy, and generalized epilepsy animal models, as well as in patients with epilepsy. However, the role and importance of HCN1 down-regulation for seizure activity is unclear. To address this question we determined the susceptibility of mice with either a general or forebrain-restricted deletion of HCN1 to limbic seizure induction by amygdala kindling or pilocarpine administration. Loss of HCN1 expression in both mouse lines is associated with higher seizure severity and higher seizure-related mortality, independent of the seizure-induction method used. Therefore, down-regulation of HCN1 associated with human epilepsy and rodent models may be a contributing factor in seizure behavior.
authors.affiliation: Department of Neuroscience, Columbia University, New York, New York, USA. bs73@columbia.edu
authors.forename: Bina
authors.initials: B
authors.lastname: Santoro
authors.forename: Janet Y
authors.initials: JY
authors.lastname: Lee
authors.forename: Dario J
authors.initials: DJ
authors.lastname: Englot
authors.forename: Sandra
authors.initials: S
authors.lastname: Gildersleeve
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Piskorowski
authors.forename: Steven A
authors.initials: SA
authors.lastname: Siegelbaum
authors.forename: Melodie R
authors.initials: MR
authors.lastname: Winawer
authors.forename: Hal
authors.initials: H
authors.lastname: Blumenfeld
mesh_terms: D000818:Animals; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000172:deficiency*; D004195:Disease Models, Animal; D006614:Hindlimb / Q000187:drug effects / Q000503:physiopathology; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007696:Kindling, Neurologic / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018721:Muscarinic Agonists / Q000009:adverse effects; D010862:Pilocarpine / Q000009:adverse effects; D015221:Potassium Channels / Q000172:deficiency*; D012640:Seizures / Q000139:chemically induced / Q000235:genetics* / Q000401:mortality* / Q000503:physiopathology*; D012720:Severity of Illness Index
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; C578665:HCN1 protein, human; C578666:Hcn1 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D018721:Muscarinic Agonists; D015221:Potassium Channels; D010862:Pilocarpine
references.citation: J Comp Neurol. 2004 Apr 5;471(3):241-76
references.pmid: 14991560
references.citation: J Neurosci. 2007 Nov 21;27(47):13012-21
references.pmid: 18032674
references.citation: J Neurosci. 2003 Jul 30;23(17):6826-36
references.pmid: 12890777
references.citation: Neuron. 2004 Oct 28;44(3):495-508
references.pmid: 15504329
references.citation: J Neurosci. 2005 Oct 26;25(43):9871-82
references.pmid: 16251434
references.citation: J Neurosci. 2002 Jun 1;22(11):4591-9
references.pmid: 12040066
references.citation: Cell. 2003 Nov 26;115(5):551-64
references.pmid: 14651847
references.citation: Neurobiol Dis. 2008 Oct;32(1):26-36
references.pmid: 18657617
references.citation: Annu Rev Physiol. 2003;65:453-80
references.pmid: 12471170
references.citation: Epilepsy Res. 2001 Dec;47(3):217-27
references.pmid: 11738929
references.citation: Mamm Genome. 2007 Jan;18(1):23-31
references.pmid: 17242861
references.citation: Epilepsia. 2009 Jan;50(1):44-55
references.pmid: 18637833
references.citation: Trends Neurosci. 2003 Oct;26(10):550-4
references.pmid: 14522148
references.citation: Clin Auton Res. 2006 Feb;16(1):18-28
references.pmid: 16477491
references.citation: Cell. 2004 Nov 24;119(5):719-32
references.pmid: 15550252
references.citation: Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):6852-5
references.pmid: 7624331
references.citation: J Neurosci. 2009 Sep 2;29(35):10979-88
references.pmid: 19726656
references.citation: Epilepsia. 2010 Mar;51(3):404-14
references.pmid: 19694789