Impaired regulation of thalamic pacemaker channels through an imbalance of subunit expression in absence epilepsy

Thomas Budde, Luigi Caputi, Tatyana Kanyshkova, Rainer Staak, Christian Abrahamczik, Thomas Munsch, Hans Christian Pape

Research output: Contribution to journalArticlepeer-review

Abstract

The role of hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channel isoforms and hyperpolarization-activated cation current (Ih) 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 Ih by Cs+ and ZD7288 (4-ethylphenylamino-1,2-dimethyl-6- methylaminopyrimidinium chloride). In vitro analyses revealed a hyperpolarizing shift of half-maximal Ih activation (Vh) in WAG/Rij (Vh = -93.2 mV) compared with nonepileptic controls [August × Copenhagen-Irish (ACI) (Vh = -88.0 mV)]. This effect is explained by a shift of the responsiveness of Ih 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, Ih 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 4 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 Ih during absence seizures.

Original languageEnglish
Pages (from-to)9871-9882
Number of pages12
JournalJournal of Neuroscience
Volume25
Issue number43
DOIs
Publication statusPublished - Oct 26 2005

Keywords

  • Absence epilepsy
  • cAMP
  • h-current
  • HCN channels
  • Spike-and-wave
  • Thalamic dysfunction

ASJC Scopus subject areas

  • Neuroscience(all)

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