Distinct perinatal features of the hyperpolarization-activated non-selective cation current I(h) in the rat cortical plate.

BACKGROUND: During neocortical development, multiple voltage- and ligand-gated ion channels are differentially expressed in neurons thereby shaping their intrinsic electrical properties. One of these voltage-gated ion channels, the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel and its current I(h), is an important regulator of neuronal excitability. Thus far, studies on an early I(h) appearance in rodent neocortex are missing or conflicting. Therefore, we focused our study on perinatal neocortical I(h) and its properties. RESULTS: In the perinatal rat neocortex we observed a rapid increase in the number of neurons exhibiting I(h). Perinatal I(h) had unique properties: first, a pronounced cAMP sensitivity resulting in a marked shift of the voltage sufficient for half-maximum activation of the current towards depolarized voltages and second, an up to 10 times slower deactivation at physiological membrane potentials when compared to the one at postnatal day 30. The combination of these features was sufficient to suppress membrane resonance in our in silico and in vitro experiments. Although all four HCN subunits were present on the mRNA level we only detected HCN4, HCN3 and HCN1 on the protein level at P0. HCN1 protein at P0, however, appeared incompletely processed. At P30 glycosilated HCN1 and HCN2 dominated. By in silico simulations and heterologous co-expression experiments of a 'slow' and a 'fast' I(h) conducting HCN channel subunit in HEK293 cells, we mimicked most characteristics of the native current, pointing to a functional combination of subunit homo- or heteromeres. CONCLUSION: Taken together, these data indicate a HCN subunit shift initiated in the first 24 hours after birth and implicate a prominent perinatal role of the phylogenetically older HCN3 and/or HCN4 subunits in the developing neocortex.

Ih is maturing: implications for neuronal development.

Vast electrophysiological activity near resting potential, including rhythmic oscillatory activity, is a hallmark of many brain regions and a motor of the developing CNS. This activity is mediated and influenced by diverse receptor-operated and voltage-gated ion channels. In turn, these channels are modulated during the course of development by altering their density, distribution and properties. The hyperpolarization-activated and cyclic nucleotide-gated cation current, Ih, impacts on the resting membrane potential and is involved in the generation and modulation of neuronal oscillatory activity. Therefore, it is conceivable that Ih is well suited to govern the specific processes involved in activity-dependent neuronal development. Here, we review the evidence that maturation of Ih accounts, at least in part, for the control of membrane properties during neuronal development of various parts of the brain. The temporal and regional variations in Ih development might underlie the normal maturation of neuronal circuits and, consequently, the perturbations of this might account for some of the neuropathology of the brain. This review summarizes the evidence for the stage and localization dependence of Ih in CNS development with a focus on arborized cells with high dendritic Ih. Further, it outlines hypotheses on the contribution of Ih to neuronal and network maturation.