Abstracts

ENHANCED EXPRESSION OF A HYPERPOLARIZATION-ACTIVATED CYCLIC NUCLEOTIDE-GATED CATION CHANNEL (HCN1) IN DENTATE GRANULE CELLS OF BOTH HUMAN AND EXPERIMENTAL TEMPORAL LOBE EPILEPSY (TLE)

Abstract number : 2.062
Submission category :
Year : 2003
Submission ID : 2150
Source : www.aesnet.org
Presentation date : 12/6/2003 12:00:00 AM
Published date : Dec 1, 2003, 06:00 AM

Authors :
Roland A. Bender, Amy L. Brewster, Heinz W. Beck, Gary W. Mathern, Tallie Z. Baram Depts Anatomy/Neurobiology & Pediatrics, University of California, Irvine, CA; Dept Epileptology, University of Bonn, Germany; Division of Neurosurgery, Reed Neurological R

Transcriptional dysregulation of hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels is emerging as contributing critically to epileptogenic processes (Brewster et al., 2002). Our recent work has suggested that changes in HCN expression might also be involved in chronic human hippocampal epilepsy. In hippocampi of patients with mesial temporal sclerosis, HCN1 mRNA expression was markedly ([sim]500%) increased in individual granule cells (GCs) once GC neuronal density was reduced by [gt]50% (Bender et al., 2002). The mechanisms for altered HCN expression and the potential consequences of the resulting channel function are difficult to study in human material. Therefore, we analyzed HCN mRNA expression in pilocarpine-treated animals, a model that closely reproduces human chronic TLE.
Wistar male rats (150-200 g) were injected with a single dose of pilocarpine (340 mg/kg i.p), and the resulting status epilepticus was terminated after 40 min. Rats developed a chronic epileptic state, and their hippocampi, harvested 30 days after treatment, were analyzed for neuronal numbers and HCN mRNA expression compared with control rats (n=5 per group).
Expression of HCN1mRNA (but not of HCN2) was significantly upregulated in individual GCs of chronically epileptic rats, as found originally in the human. GC cell loss in the animal model was relatively modest (20%), but, as in the human, changes in HCN1 expression were accompanied by a striking (55%) reduction of hilar neurons.
HCN1 mRNA levels are increased in GCs in both human and experimental TLE. The strong correlation of this channel upregulation with severe loss of hilar neurons and/or GCs suggests that it might be driven by the altered circuitries of the dentate gyrus. Reduced hyperpolarizing input (and channel activation), coupled with increased dendritic excitation of surviving GCs, might provoke a [lsquo]compensatory[apos] enhancement of HCN1 mRNA and protein expression. The pilocarpine model thus provides a suitable tool to study the regulatory mechanisms as well as the consequences of an altered HCN1 expression in the epileptic hippocampal network.
[Supported by: EFA/Milken Foundation (RAB), NS35439 (TZB), NS28912 (ALB, TZB), NS02808, NS38992 (GWM)]