Hyperpolarization-activated cation channels inhibit EPSPs by interactions with M-type K(+) channels

The processing of synaptic potentials by neuronal dendrites depends on both their passive cable properties and active voltage-gated channels, which can generate complex effects due to their nonlinear properties. In this study, we characterized the actions of the hyperpolarization-activated cation current (I(h)) on dendritic processing of subthreshold excitatory postsynaptic potentials (EPSPs) in mouse CA1 hippocampal neurons. Although I(h) generates an excitatory inward current that exerted a direct depolarizing effect on the peak voltage of weak EPSPs, it produced a paradoxical hyperpolarizing effect on the peak voltage of stronger but still subthreshold EPSPs. Using a combined modeling and experimental approach, we found that the inhibitory action of I(h) is caused by its interaction with the delayed rectifier M-type K(+) current. In this manner, I(h) can enhance spike firing in response to an EPSP when spike threshold is low but inhibit firing when spike threshold is high.