During slow-wave sleep, thalamocortical relay (TC) neurons display intrinsic pacemaker activity, leading to the rhythmic generation of bursts of action potentials, which are synchronized throughout the thalamocortical network. It is known that this pace-making property strongly depends on the hyperpolarization-activated inward current I_h (HCN channels). So how can this work in younger animals with considerably less I_h?

We combined electrophysiological, molecular, immunohistochemical, EEG recordings in vivo, and computer modeling techniques to examine HCN gene expression and I_h properties in rat TC neurons in the dorsal part of the lateral geniculate nucleus and the functional consequence of this maturation.

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 concentration. 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.