Differential regulation of HCN channel isoform expression in thalamic neurons of epileptic and non-epileptic rat strains

Tatyana Kanyshkova, Patrick Meuth, Pawan Bista, Zhiqiang Liu, Petra Ehling, Luigi Caputi, Michael Doengi, Dane M. Chetkovich, Hans Christian Pape, Thomas Budde

Research output: Contribution to journalArticle

Abstract

Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels represent the molecular substrate of the hyperpolarization-activated inward current (I h). Although these channels act as pacemakers for the generation of rhythmic activity in the thalamocortical network during sleep and epilepsy, their developmental profile in the thalamus is not yet fully understood. Here we combined electrophysiological, immunohistochemical, and mathematical modeling techniques to examine HCN gene expression and I h properties in thalamocortical relay (TC) neurons of the dorsal part of the lateral geniculate nucleus (dLGN) in an epileptic (WAG/Rij) compared to a non-epileptic (ACI) rat strain. Recordings of TC neurons between postnatal day (P) 7 and P90 in both rat strains revealed that I h was characterized by higher current density, more hyperpolarized voltage dependence, faster activation kinetics, and reduced cAMP-sensitivity in epileptic animals. All four HCN channel isoforms (HCN1-4) were detected in dLGN, and quantitative analyses revealed a developmental increase of protein expression of HCN1, HCN2, and HCN4 but a decrease of HCN3. HCN1 was expressed at higher levels in WAG/Rij rats, a finding that was correlated with increased expression of the interacting proteins filamin A (FilA) and tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b). Analysis of a simplified computer model of the thalamic network revealed that the alterations of I h found in WAG/Rij rats compensate each other in a way that leaves I h availability constant, an effect that ensures unaltered cellular burst activity and thalamic oscillations. These data indicate that during postnatal developmental the hyperpolarizing shift in voltage dependency (resulting in less current availability) is compensated by an increase in current density in WAG/Rij thereby possibly limiting the impact of I h on epileptogenesis. Because HCN3 is expressed higher in young versus older animals, HCN3 likely does not contribute to alterations in I h in older animals.

Original languageEnglish
Pages (from-to)450-461
Number of pages12
JournalNeurobiology of Disease
Volume45
Issue number1
DOIs
Publication statusPublished - Jan 2012

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Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
Cyclic Nucleotide-Gated Cation Channels
Geniculate Bodies
Protein Isoforms
Neurons
Inbred ACI Rats
Filamins
Proteins
Cyclic Nucleotides
Thalamus
Computer Simulation
Cations
Epilepsy
Sleep
Gene Expression

Keywords

  • Absence epilepsy
  • Computer modeling
  • H-current
  • Thalamic dysfunction
  • Thalamocortical relay neurons

ASJC Scopus subject areas

  • Neurology

Cite this

Differential regulation of HCN channel isoform expression in thalamic neurons of epileptic and non-epileptic rat strains. / Kanyshkova, Tatyana; Meuth, Patrick; Bista, Pawan; Liu, Zhiqiang; Ehling, Petra; Caputi, Luigi; Doengi, Michael; Chetkovich, Dane M.; Pape, Hans Christian; Budde, Thomas.

In: Neurobiology of Disease, Vol. 45, No. 1, 01.2012, p. 450-461.

Research output: Contribution to journalArticle

Kanyshkova, T, Meuth, P, Bista, P, Liu, Z, Ehling, P, Caputi, L, Doengi, M, Chetkovich, DM, Pape, HC & Budde, T 2012, 'Differential regulation of HCN channel isoform expression in thalamic neurons of epileptic and non-epileptic rat strains', Neurobiology of Disease, vol. 45, no. 1, pp. 450-461. https://doi.org/10.1016/j.nbd.2011.08.032
Kanyshkova, Tatyana ; Meuth, Patrick ; Bista, Pawan ; Liu, Zhiqiang ; Ehling, Petra ; Caputi, Luigi ; Doengi, Michael ; Chetkovich, Dane M. ; Pape, Hans Christian ; Budde, Thomas. / Differential regulation of HCN channel isoform expression in thalamic neurons of epileptic and non-epileptic rat strains. In: Neurobiology of Disease. 2012 ; Vol. 45, No. 1. pp. 450-461.
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AU - Ehling, Petra

AU - Caputi, Luigi

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