Postnatal development of the hyperpolarization-activated excitatory current Ih in mouse hippocampal pyramidal neurons

The hyperpolarization-activated excitatory current I(h) shapes rhythmic firing and other components of excitability in differentiating neurons, and may thus influence activity-dependent CNS development. We therefore studied developmental changes in I(h) and underlying hyperpolarization-activated cyclic nucleotide-gated (HCN) channel subunits in pyramidal neurons of neonatal mouse hippocampus using electrophysiological and immunofluorescence approaches. I(h) conductance (at -80 mV) tripled in CA3 neurons and quintupled in CA1 neurons between postnatal day 1 (P1) and P20; parallel changes in membrane area resulted in current density maxima at P5 in CA3 and P10 in CA1. Concurrently, I(h) activation times fell sevenfold in CA3 and 10-fold in CA1. A computational model indicates that a decrease in I(h) activation time will increase the rhythmic firing rate. Two mechanisms contributed to more rapid I(h) activation at P20 in CA3 and CA1 neurons: a fall in the intrinsic time constants of two kinetic components, tau(fast) and tau(slow), to 35-40% (at -90 mV) of their P1 values, and a preferential increase in fast component amplitude and contribution to I(h) (from approximately 35% to approximately 74% of total). HCN1, HCN2, and HCN4 immunoreactivities showed independent temporal and spatial developmental patterns. HCN1 immunoreactivity was low at P1 and P5 and increased by P20. HCN2 immunoreactivity was detected at P1 and increased steadily up to P20. HCN4 immunoreactivity was initially low and showed a small increase by P20. We suggest that developmental increases in I(h) amplitude and activation rate reflect changes in the number and underlying structure of I(h) channels, and that I(h) maturation may shape rhythmic activity important for hippocampal circuit maturation.