Abstracts

RATIONALE: Hyperpolarization-activated cation currents (I[sub]h[/sub]) are present in brain regions including thalamus and hippocampus and serve important functions in network synchronization and neuronal membrane properties. The molecular basis of these currents involves hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels. HCN channel protein isoforms are encoded by at least 4 different genes (HCN1-4) that govern the regulation and kinetics of the resulting channels. Prolonged febrile seizures, experimentally induced in immature rats, have recently been shown to persistently alter the properties of HCN channels in the developing rat hippocampus (Chen et al., 2001, Nat. Med. 7, 331-337). Because the functional properties of HCN channels may depend on their isoform make-up, understanding the mechanisms that underly this altered function requires information about the expression and distribution of the 4 HCN isoforms in the developing rat hippocampus.
METHODS: Nonradioactive in situ hybridization (single or in combination with immunocytochemistry) was used to determine the spatial and temporal expression patterns of HCN isoforms in the rat hippocampus.
RESULTS: HCNs 1, 2 and 4 (but not 3) mRNAs were differentially expressed in interneuronal and principal cell populations of the rat hippocampus. Expression profiles of each isoform evolved during postnatal development, and patterns observed during early postnatal ages differed significantly from those in mature hippocampus: HCN1 mRNA, expressed in CA1 but not in CA3 pyramidal cells in the adult, was present in both CA1 and CA3 pyramidal cells during the first two postnatal weeks; HCN4 mRNA was expressed only in CA1 pyramidal cells in immature hippocampus, but was progressively expressed throughout the pyramidal cell layer upon maturation. In interneurons, onset of HCN expression in the hippocampus proper preceded that in the dentate gyrus, suggesting that HCN-mediated pacing activity may be generated in hippocampal interneurons prior to those in the hilus. Selectivity of HCN expression in interneurons was evident also by preferential expression of HCN1 mRNA in basket cells, and of HCN2 and HCN4 mRNA in CA1 stratum oriens/alveus neurons.
CONCLUSIONS: HCN expression patterns involve isoform-specific, age-dependent spatio-temporal evolution in distinct hippocampal cell populations, suggesting that these channels serve differing and changing functions in the maturation of coordinated hippocampal activity. Disturbance of this process during development, e.g, by age-specific (prolonged febrile) seizures, may alter the normal spatiotemporal expression (and thus age-specific roles) of these channel molecules, leading to long-term functional consequences.
Support: NS35439 (T.Z.B.) and Epilepsy Foundation of America (R.A.B.)