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The Journal of Neuroscience, July 8, 2009, 29(27):8847-8857; doi:10.1523/JNEUROSCI.0689-09.2009

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Cellular/Molecular
Postnatal Expression Pattern of HCN Channel Isoforms in Thalamic Neurons: Relationship to Maturation of Thalamocortical Oscillations

Tatyana Kanyshkova,^1 * Matthias Pawlowski,^1 * Patrick Meuth,^1 * Celine Dubé,² Roland A. Bender,^2,3 Amy L. Brewster,^2,4 Arnd Baumann,⁵ Tallie Z. Baram,² Hans-Christian Pape,¹ and Thomas Budde¹

¹Institut für Physiologie I, Westfälische Wilhelms-Universität Münster, D-48149 Münster, Germany, ²Anatomy/Neurobiology and Pediatrics, University of California, Irvine, California 92697-4475, ³Institut für Anatomie I, Universitätsklinikum Hamburg-Eppendorf, D-20246 Hamburg, Germany, ⁴Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, and ⁵Institut für Strukturbiologie und Biophysik 1, Forschungszentrum Jülich, D-52425 Jülich, Germany

Correspondence should be addressed to Thomas Budde, Institut für Physiologie I, Westfälische Wilhelms-Universität Münster, Robert-Koch-Strasse 27a, D-48149 Münster, Germany. Email: tbudde{at}uni-muenster.de

Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels are the molecular substrate of the hyperpolarization-activated inward current (I_h). Because the developmental profile of HCN channels in the thalamus is not well understood, we combined electrophysiological, molecular, immunohistochemical, EEG recordings in vivo, and computer modeling techniques to examine HCN gene expression and I_h properties in rat thalamocortical relay (TC) neurons in the dorsal part of the lateral geniculate nucleus and the functional consequence of this maturation. Recordings of TC neurons revealed an approximate sixfold increase in I_h density between postnatal day 3 (P3) and P106, which was accompanied by significantly altered current kinetics, cAMP sensitivity, and steady-state activation properties. Quantification on tissue levels revealed a significant developmental decrease in cAMP. Consequently the block of basal adenylyl cyclase activity was accompanied by a hyperpolarizing shift of the I_h activation curve in young but not adult rats. Quantitative analyses of HCN channel isoforms revealed a steady increase of mRNA and protein expression levels of HCN1, HCN2, and HCN4 with reduced relative abundance of HCN4. Computer modeling in a simplified thalamic network indicated that the occurrence of rhythmic delta activity, which was present in the EEG at P12, differentially depended on I_h conductance and modulation by cAMP at different developmental states. These data indicate that the developmental increase in I_h density results from increased expression of three HCN channel isoforms and that isoform composition and intracellular cAMP levels interact in determining I_h properties to enable progressive maturation of rhythmic slow-wave sleep activity patterns.

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Received Feb. 10, 2009; revised April 23, 2009; accepted May 20, 2009.

Correspondence should be addressed to Thomas Budde, Institut für Physiologie I, Westfälische Wilhelms-Universität Münster, Robert-Koch-Strasse 27a, D-48149 Münster, Germany. Email: tbudde{at}uni-muenster.de

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