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This Article Full Text Full Text (PDF) All Versions of this Article: 575/1/83    most recent jphysiol.2006.110486v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kuisle, M. Articles by Lüthi, A. Search for Related Content PubMed PubMed Citation Articles by Kuisle, M. Articles by Lüthi, A. Related Collections Neuroscience

¹ Department of Pharmacology and Neurobiology, Biozentrum, Klingelbergstr. 70, CH-4056 Basel, Switzerland
² Departments of Anatomy/Neurobiology and Pediatrics, University of California at Irvine, Irvine, CA 92697, USA
³ INSERM U666, Physiopathologie clinique et expérimentale de la schizophrénie, Faculté de Médecine, 11 rue Humann, F-67085, Strasbourg, France

Aberrant function of pacemaker currents (I_h), carried by hyperpolarization-activated cation non-selective (HCN) channels, affects neuronal excitability and accompanies epilepsy, but its distinct roles in epileptogenesis and chronic epilepsy are unclear. We probed I_h function and subunit composition during both pre- and chronically epileptic stages in thalamocortical (TC) neurones of the Genetic Absence Epilepsy Rat from Strasbourg (GAERS). Voltage gating of I_h was unaltered in mature somatosensory TC cells, both in vivo and in vitro. However, the enhancement of I_h by phasic, near-physiological, cAMP pulses was diminished by 40% and the half-maximal cAMP concentration increased by 5-fold. This decreased responsiveness of I_h to its major cellular modulator preceded epilepsy onset in GAERS, persisted throughout the chronic state, and was accompanied by an enhanced expression of the cAMP-insensitive HCN1 channel mRNA (> 50%), without changes in the mRNA levels of HCN2 and HCN4. To assess for alterations in TC cell excitability, we monitored the slow up-regulation of I_h that is induced by Ca²⁺-triggered cAMP synthesis and important for terminating in vitro synchronized oscillations. Remarkably, repetitive rebound Ca²⁺ spikes evoked normal slow I_h up-regulation in mature GAERS neurones; that sufficed to attenuate spontaneous rhythmic burst discharges. These adaptive mechanisms occurred upstream of cAMP turnover and involved enhanced intracellular Ca²⁺ accumulation upon repetitive low-threshold Ca²⁺ discharges. Therefore, HCN channels appear to play a dual role in epilepsy. Weakened cAMP binding to HCN channels precedes, and likely promotes, epileptogenesis in GAERS, whereas compensatory mechanisms stabilizing I_h function contribute to the termination of spike-and-wave discharges in chronic epilepsy.

(Received 5 April 2006; accepted after revision 23 May 2006; first published online 25 May 2006)
Corresponding author A. Lüthi: Department of Pharmacology and Neurobiology, Klingelbergstr. 70, CH-4056 Basel, Switzerland. Email: anita.luthi{at}unibas.ch

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