Hyperpolarization-activated cation currents, termed If, Ih, or Iq, were initially discovered in heart and nerve cells over 20 years ago. These currents contribute to a wide range of physiological functions, including cardiac and neuronal pacemaker activity, the setting of resting potentials, input conductance and length constants, and dendritic integration. The hyperpolarization-activated, cation nonselective (HCN) gene family encodes the channels that underlie Ih. Here we review the relation between the biophysical properties of recombinant HCN channels and the pattern of HCN mRNA expression with the properties of native Ih in neurons and cardiac muscle. Moreover, we consider selected examples of the expanding physiological functions of Ih with a view toward understanding how the properties of HCN channels contribute to these diverse functional roles.

Summary The hippocampus is critical for encoding declarative memory, our repository of knowledge of who, what, where, and when1. Mnemonic information is processed in the hippocampus through several parallel routes involving distinct subregions. In the classic trisynaptic pathway, information proceeds from entorhinal cortex (EC) to dentate gyrus (DG) to CA3 and then to CA1, the main hippocampal output2. Genetic lesions of EC3 and hippocampal DG4, CA35, and CA16 regions have revealed their distinct functions in learning and memory. In contrast, little is known about the role of CA2, a relatively small area interposed between CA3 and CA1 that forms the nexus of a powerful disynaptic circuit linking EC input with CA1 output7. Here, we report a novel transgenic mouse line that enabled us to selectively examine the synaptic connections and behavioral role of the CA2 region in adult mice. Genetically targeted inactivation of CA2 pyramidal neurons caused a pronounced loss of social memory, the ability of an animal to remember a conspecific, with no change in sociability or several other hippocampal-dependent behaviors, including spatial and contextual memory. These behavioral and anatomical results thus reveal CA2 as a critical hub of sociocognitive memory processing.

The hyperpolarization-activated cation current (termed I h , I q , or I f ) was recently shown to be encoded by a new family of genes, named HCN for hyperpolarization-activated cyclic nucleotidesensitive cation nonselective. When expressed in heterologous cells, each HCN isoform generates channels with distinct activation kinetics, mirroring the range of biophysical properties of native I h currents recorded in different classes of neurons. To determine whether the functional diversity of I h 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 native I h currents in hippocampal and thalamic neurons, our data support the idea that the functional heterogeneity of I h channels is attributable, in part, to differential isoform expression. Moreover, in some neurons, specific functional roles can be proposed for I h channels with defined subunit composition.