The Excitatory and Inhibitory Effects of the Hyperpolarization-Activated Cation Current on Neuronal Activity: Resolution of a Paradox

Neurons possess a constellation of voltage-gated ion channels that determine their integrative properties and regulate their output. The nonlinear voltage-dependent kinetics and spatial distributions of these channels generate complex effects on subthreshold and suprathreshold signals. These effects ultimately shape action potential output at the soma. To understand how some of these nonlinear interactions arise, we focus on the role of the hyperpolarization-activated cation current (Ih) and the mechanisms by which it influences the activity of other voltage-gated currents. These mechanisms are investigated with computational neuronal models and are tested experimentally in hippocampal CA1 pyramidal neurons. Ih provides an excitatory current at subthreshold potentials, but paradoxically, has been associated with an inhibitory effect on neuronal signals. We use computational models to demonstrate that in the absence of other voltage-gated conductances, Ih exerts a positive influence on input signals that should promote excitability. Using whole-cell recordings, we then characterize the actions of Ih on dendritic processing of subthreshold excitatory postsynaptic potentials (EPSPs) elicited by stimulation of the Schaffer collateral inputs to CA1 pyramidal neurons. We describe a novel nonlinear interaction with the M-type K+ current (IM), whereby Ih generates a direct excitatory effect on the peak voltage of weak EPSPs, but produces a paradoxical inhibitory effect on the peak voltage of strong EPSPs. This interaction arises from the action of Ih to depolarize the resting membrane, which enhances activation of IM. In this manner, the interplay of Ih and IM can enhance the firing of neurons by an EPSP when spike threshold is low but inhibit neuronal firing when spike threshold is high. Furthermore, we show in a neuronal model that modulation of IM regulates the extent of the excitatory--inhibitory regimes of Ih. To assess the influence of Ih on suprathreshold signals, we obtain somatic whole-cell recordings from CA1 pyramidal neurons and show that Ih suppresses spiking and increases Na+ action potential threshold. Using computational models, we provide evidence that Ih indirectly enhances the level of resting Na+ channel inactivation by depolarizing the resting membrane. In addition, Ih slows the rate of rise of the membrane voltage in response to depolarizing ramp currents by decreasing the input resistance of the neuron. The combined effects of Ih to increase resting Na+ channel inactivation and slow the rate of membrane depolarization elevate threshold and thereby reduce spiking. Finally, we also find that the Ih-induced activation of IM and inactivation of Na + channels act in conjunction to further suppress action potential generation. Interestingly, both complex interactions we describe are linked to the influence of Ih on the resting membrane potential. We propose that these findings represent a general mechanism in pyramidal neurons by which neuromodulators that affect Ih alter the resting membrane potential and consequently regulate subthreshold and suprathreshold excitability.