Altered Expression of Hyperpolarization-Activated Cyclic-Nucleotide-Regulated Cation Channel (HCN) Isoforms after Prolonged Experimental Febrile Seizures Correlates with Excitability-Promoting Changes of Channel Function: An Acquired Channelopathy?
Abstract number :
2.001
Submission category :
Year :
2001
Submission ID :
248
Source :
www.aesnet.org
Presentation date :
12/1/2001 12:00:00 AM
Published date :
Dec 1, 2001, 06:00 AM
Authors :
A. Brewster, BSc, Anatomy/Neurobiology and Pediatrics, University of California at Irvine, Irvine, CA; R.A. Bender, PhD, Anatomy/Neurobiology and Pediatrics, University of California at Irvine, Irvine, CA; M. Eghbal-Ahmadi, MSc, Anatomy/Neurobiology and P
RATIONALE: Currents mediated by hyperpolarization-activated, cyclic nucleotide-gated cation channels (HCNs) contribute to the regulation of neuronal membrane-potential and coordinated firing in the hippocampal formation. However, while the roles of these channels in normal hippocampal function is increasingly being recognized, the contribution of altered HCNs to the process of epileptogenesis has not been elucidated. Recent work (Chen et al., Nature Medicine, 2001;7:331-337) has demonstrated that alterations in functional properties of the currents (I[sub]H[/sub]) mediated by HCNs are required and sufficient to increase activity-dependent hyperexcitability in the hippocampal circuit following a single episode of experimental febrile seizures. Three HCN subunit isoforms, each encoding channels with distinct functional properties, are expressed in early postnatal hippocampus, including the stage of maturation when experimental febrile seizures can be induced (Bender et al., abstract in this meeting). Therefore, these studies tested the hypothesis that experimental febrile seizures modified the relative expression of these HCN isoforms, resulting in channels with slower kinetics and altered voltage activation curves.
METHODS: Using both semi-quantitative as well as non-radioactive in situ hybridization, HCN1, 2 and 4 were mapped to CA1 pyramidal cells, as well as to discrete interneuronal populations. The mRNA levels of these transcripts in animals experiencing a ~20 minute hyperthermic seizure were compared to those in controls at several time-points.
RESULTS: Following hyperthermic seizures on P10, a significant reduction of the fast-kinetics HCN1 isoform was observed in CA1 and subiculum on P17 and P24, whereas increased expression of the slow-kinetics HCN4 occurred in the same regions. No change in the expression of HCN2, the predominant thalamic HCN isoform was found.
CONCLUSIONS: These data show that during development, a single perturbation of [soquote]normal[ssquote] activity may modify the programmed expression of channel protein genes, resulting in channel dysfunction and hippocampal hyperexcitability.
Support: NIH NS35439 [TZB]; NS 28912-S1 [AB & TZB] and an AES postdoctoral fellowship award [RAB].