Increased seizure severity and seizure-related death in mice lacking HCN1 channels.
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.
Santoro
Bina
B
Department of Neuroscience, Columbia University, New York, New York, USA. bs73@columbia.edu
Lee
Janet Y
JY
Englot
Dario J
DJ
Gildersleeve
Sandra
S
Piskorowski
Rebecca A
RA
Siegelbaum
Steven A
SA
Winawer
Melodie R
MR
Blumenfeld
Hal
H
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
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
J Comp Neurol. 2004 Apr 5;471(3):241-76
14991560
J Neurosci. 2007 Nov 21;27(47):13012-21
18032674
J Neurosci. 2003 Jul 30;23(17):6826-36
12890777
Neuron. 2004 Oct 28;44(3):495-508
15504329
J Neurosci. 2005 Oct 26;25(43):9871-82
16251434
J Neurosci. 2002 Jun 1;22(11):4591-9
12040066
Cell. 2003 Nov 26;115(5):551-64
14651847
Neurobiol Dis. 2008 Oct;32(1):26-36
18657617
Annu Rev Physiol. 2003;65:453-80
12471170
Epilepsy Res. 2001 Dec;47(3):217-27
11738929
Mamm Genome. 2007 Jan;18(1):23-31
17242861
Epilepsia. 2009 Jan;50(1):44-55
18637833
Trends Neurosci. 2003 Oct;26(10):550-4
14522148
Clin Auton Res. 2006 Feb;16(1):18-28
16477491
Cell. 2004 Nov 24;119(5):719-32
15550252
Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):6852-5
7624331
J Neurosci. 2009 Sep 2;29(35):10979-88
19726656
Epilepsia. 2010 Mar;51(3):404-14
19694789