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

Abstract

Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels are the molecular substrate of the hyperpolarizationactivated 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.

Decreased hyperpolarization-activated currents in layer 5 pyramidal neurons enhances excitability in focal cortical dysplasia

“…A reduction in I h and increased dendritic EPSP summation also have been observed after status epilepticus induced by kainic acid (Shin et al 2008). Similarly, the spontaneously epileptic WAG/Rij rat exhibits reduced I h associated with increased R in and enhanced synaptic summation (Kole et al 2007;Strauss et al 2004). Perinatal seizures induced by hypoxia are also accompanied by a downregulation of I h (Zhang et al 2006).…”

“…Depending on the cell type and brain region, the inwardly rectifying hyperpolarization-activated current I h contributes to generation of rhythmic activity (McCormick and Pape 1990), determination of the resting membrane potential (Robinson and Siegelbaum 2003), and synaptic integration (Magee 2000;Berger et al 2001). Alterations in I h and HCN expression occur in a variety of seizure models including kainic acid-and pilocarpine-induced epilepsy (Jung et al 2007;Shin et al 2008), early-life hyperthermia (Chen et al 2001), temporal lobe kindling (Powell et al 2008), and absence seizures (Kole et al 2007;Schridde et al 2006;Strauss et al 2004). HCN1 subunitspecific knockout mice have a reduced seizure threshold (Huang et al 2009), whereas HCN2 knockout mice exhibit an absence epilepsy phenotype (Ludwig et al 2003).…”

“…Maturation of rhythmic slow-wave sleep activity patterns is dependent on the density and the properties of I h during development (Kanyshkova et al 2009). Working memory networks are strengthened by inhibition of HCN channel signaling in prefrontal cortex (Wang et al 2007).…”

Nicotine Blocks the Hyperpolarization-Activated CurrentIhand Severely Impairs the Oscillatory Behavior of Oriens-Lacunosum Moleculare Interneurons

“…Changes in homomeric and heteromeric expression of HCN subunits would determine differences in the biophysical properties of I h as well as its sensitivity to cAMP (Pedarzani and Storm, 1995;Santoro et al, 1998;Kanyshkova et al, 2009). To assess whether native HCN channels present on O-LM interneurons contain the cAMP-sensitive subunits, hyperpolarizing voltage steps of increasing amplitude were delivered in the absence or presence of forskolin (n ϭ 8), which activates adenylate cyclase, or in the presence of the long-acting cAMP derivative Br-cAMP (n ϭ 4).…”

Postnatal development of synaptic properties of the GABAergic projection from the inferior colliculus to the auditory thalamus

“…The persistence of V rest differences with age despite the use of consistent intracellular solutions argues for differences in the number or function of ion channels. Such changes have been observed in the thalamus and other auditory nuclei, in hyperpolarization-activated cation channels (Kanyshkova et al 2009), KCC2 (Blaesse et al 2006), and the Na (Yan et al 2001), to name a few.…”