Molecular and Functional Heterogeneity of Hyperpolarization-Activated Pacemaker Channels in the Mouse CNS

Abstract

The hyperpolarization-activated cation current (termedIh,Iq, orIf) was recently shown to be encoded by a new family of genes, named HCN forhyperpolarization-activated cyclicnucleotide-sensitive cationnonselective. When expressed in heterologous cells, each HCN isoform generates channels with distinct activation kinetics, mirroring the range of biophysical properties of nativeIh currents recorded in different classes of neurons. To determine whether the functional diversity ofIh currents is attributable to different patterns of HCN gene expression, we determined the mRNA distribution across different regions of the mouse CNS of the three mouse HCN genes that are prominently expressed there (mHCN1, 2 and 4). We observe distinct patterns of distribution for each of the three genes. Whereas mHCN2 shows a widespread expression throughout the CNS, the expression of mHCN1 and mHCN4 is more limited, and generally complementary. mHCN1 is primarily expressed within neurons of the neocortex, hippocampus, and cerebellar cortex, but also in selected nuclei of the brainstem. mHCN4 is most highly expressed within neurons of the medial habenula, thalamus, and olfactory bulb, but also in distinct neuronal populations of the basal ganglia. Based on a comparison of mRNA expression with an electrophysiological characterization of nativeIh currents in hippocampal and thalamic neurons, our data support the idea that the functional heterogeneity ofIh channels is attributable, in part, to differential isoform expression. Moreover, in some neurons, specific functional roles can be proposed for Ihchannels with defined subunit composition.