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The Journal of Neuroscience, October 26, 2005, 25(43):9871-9882; doi:10.1523/JNEUROSCI.2590-05.2005

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Behavioral/Systems/Cognitive
Impaired Regulation of Thalamic Pacemaker Channels through an Imbalance of Subunit Expression in Absence Epilepsy

Thomas Budde,^1 * Luigi Caputi,^3 * Tatyana Kanyshkova,^3 * Rainer Staak,³ Christian Abrahamczik,³ Thomas Munsch,³ and Hans-Christian Pape²

¹Institut für Experimentelle Epilepsieforschung and ²Institut für Physiologie I, Westfälische Wilhelms-Universität Münster, D-48149 Münster, Germany, and ³Institut für Physiologie, Otto-von-Guericke-Universität Magdeburg, D-39120 Magdeburg, Germany

The role of hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channel isoforms and hyperpolarization-activated cation current (I_h) for seizure-related burst firing in thalamocortical (TC) neurons was investigated in a rat genetic model of absence epilepsy [Wistar Albino Glaxo rats, bred in Rijswijk (WAG/Rij)]. Burst discharges in TC neurons locked to seizure activity in vivo were prolonged during blockade of I_h by Cs⁺ and ZD7288 (4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride). In vitro analyses revealed a hyperpolarizing shift of half-maximal I_h activation (V_h) in WAG/Rij (V_h = -93.2 mV) compared with nonepileptic controls [August x Copenhagen-Irish (ACI) (V_h = -88.0 mV)]. This effect is explained by a shift of the responsiveness of I_h to cAMP toward higher concentrations in TC neurons from WAG/Rij, as revealed by application of 8-bromo-cAMP and the phosphodiesterase inhibitor IBMX. During blockade of adenylyl cyclase activity, I_h activation was similar in the two strains, whereas the difference in cAMP responsiveness persisted, thereby voting against different ambient cAMP levels between strains. Increasing the intracellular cAMP level and shifting I_h activation led to a change from burst to tonic firing mode in WAG/Rij but not in ACI rats. Furthermore, HCN1 expression was significantly increased on mRNA and protein levels, with no changes in HCN2-4 expression. In conclusion, there is an increase in HCN1 expression in the epileptic thalamus, associated with a decrease in cAMP responsiveness of I_h in TC neurons and resulting impairment to control the shift from burst to tonic firing, which, in turn, will prolong burst activity after recruitment of I_h during absence seizures.

Key words: absence epilepsy; h-current; HCN channels; thalamic dysfunction; spike-and-wave; cAMP

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Received Jan 28, 2005; revised September 5, 2005; accepted September 6, 2005.

This article has been cited by other articles:

				M. H.P. Kole, A. U. Brauer, and G. J. Stuart Inherited cortical HCN1 channel loss amplifies dendritic calcium electrogenesis and burst firing in a rat absence epilepsy model J. Physiol., January 15, 2007; 578(2): 507 - 525. [Abstract] [Full Text] [PDF]

				S. G. Meuth, T. Kanyshkova, P. Meuth, P. Landgraf, T. Munsch, A. Ludwig, F. Hofmann, H.-C. Pape, and T. Budde Membrane Resting Potential of Thalamocortical Relay Neurons Is Shaped by the Interaction Among TASK3 and HCN2 Channels J Neurophysiol, September 1, 2006; 96(3): 1517 - 1529. [Abstract] [Full Text] [PDF]

				M. Kuisle, N. Wanaverbecq, A. L. Brewster, S. G. A. Frere, D. Pinault, T. Z. Baram, and A. Luthi Functional stabilization of weakened thalamic pacemaker channel regulation in rat absence epilepsy J. Physiol., August 15, 2006; 575(1): 83 - 100. [Abstract] [Full Text] [PDF]

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