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 (Ih) on dendritic processing of subthreshold excitatory postsynaptic potentials (EPSPs) in mouse CA1 hippocampal neurons. Although Ih 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 Ih is caused by its interaction with the delayed rectifier M-type K+ current. In this manner, Ih can enhance spike firing in response to an EPSP when spike threshold is low but inhibit firing when spike threshold is high