Ih from synapses to networks: HCN channel functions and modulation in neurons

Abstract

Hyperpolarization-activated cyclic nucleotide gated (HCN) channels and the current they carry, I_h, are widely and diversely distributed in the central nervous system (CNS). The distribution of the four subunits of HCN channels is variable within the CNS, within brain regions, and often within subcellular compartments. The precise function of I_h can depend heavily on what other channels are co-expressed. In this review, we give an overview of HCN channel structure, distribution, and modulation by cyclic adenosine monophosphate (cAMP). We then discuss HCN channel and I_h functions, where we have parsed the roles into two main effects: a steady effect on maintaining the resting membrane potential at relatively depolarized values, and slow channel dynamics. Within this framework, we discuss I_h involvement in resonance, synaptic integration, transmitter release, plasticity, and point out a special case, where the effects of I_h on the membrane potential and its slow channel dynamics have dual roles in thalamic neurons.

Keywords: Dendritic integration; Membrane potential; Neurotransmitter release; Plasticity; Resonance; Subcellular distribution.

Figure 1.

Effects of HCN channel activation on neuronal excitability. A1) current clamp recordings from a CA1 pyramidal neuron in response to 500 ms current hyperpolarizing and depolarizing steps (−200 to 100 pA). Notice the characteristic sag during the 200 pA-hyperpolarizing step, as well as the fact that the neuron reaches the threshold for action potential initiation for the 100 pA-depolarizing current injection. A2) the perfusion of ZD7288 (20 μM) causes a hyperpolarization of the membrane potential, as well the removal of the sag during hyperpolarization. As a consequence of an increase in the input resistance, the voltage change is larger, particularly at steady state because of the sag removal. A3) when ZD7288 hyperpolarization is compensated by the injection of tonic current to overcome loss of I_h’s contribution of the resting membrane potential, the larger depolarizing step generates more action potentials than in control conditions, due to the larger input resistance. The difference in voltage displacement between control conditions and ZD7288 is made clearer by comparing the orange arrows in the two conditions. B) Model simulation to show the time course of the changes in the voltage (B1), h-current (I_h, B2), and h-conductance (g_h, B3), in a multicompartmental model of a CA1 pyramidal neuron a during a 500-ms long hyperpolarizing current injection (−200 pA). Units in B2 and B3 are expressed as current and conductance densities, respectively. Details are in the text.

Figure 2.

The contribution of HCN to neuronal functions can be divided into contribution of I_h to the steady effect on the membrane potential (blue circles), slow dynamics (red circles), or a combination of both (purple circle). Detailed descriptions of each phenomenon can be found in the text. A) I_h stabilizes the membrane potential after inhibitory input in Purkinje neurons; this effect is eliminated in HCN1 knockout mice (modified, with permission, from Nolan et al., 2003). B) I_h depolarizes the resting membrane potential in distal dendrites of CA1 pyramidal neurons indirectly shortening dendritic calcium spikes; in HCN1 knockout mice the plateaus are longer (modified, with permission, from Tsay et al., 2007). C) the slow kinetics of I_h allow for subthreshold oscillations in entorhinal cortex layer III stellate cells; oscillations are abolished when I_h is blocked (modified, with permission, from Giocomo and Hasselmo, 2008). D) in principal neurons of the medial superior olive, the window for coincidence detection is sharpened by I_h; the window widens when I_h is blocked (modified, with permission, from Khurana et al., 2011). E) the slow deactivation of I_h curtails EPSPs in distal dendrites of pyramidal CA1 neurons, such that temporal summation is much larger when I_h is blocked (modified, with permission, from Medinilla et al., 2013). F) in cerebellar mossy fibers, I_h opposes hyperpolarization in the axon, allowing for high frequency firing that fails when I_h is blocked (modified, with permission, from Byczkowicz et al., 2019). G) I_h depolarizes the presynaptic terminal of certain synapses in entorhinal cortex layer III, indirectly inhibiting glutamate release; release increases when I_h is blocked (modified, with permission, from Huang et al., 2011). H) I_h in the axons and terminals of cerebellar basket cells depolarizes the membrane potential and increases GABA release; release decreases when I_h is blocked (modified, with permission, from Southan et al., 2000). I) a slow I_h-dependent depolarization in thalamocortical relay neurons (left) allows T-type Ca²⁺ activation and a burst of Na⁺/K⁺ action potentials. Tonic firing (right) ensues when the membrane potential is depolarized to simulate larger I_h activation (modified, with permission, from McCormick and Pape, 1990a).

Figure 3.

Contribution of I_h to the resonance properties of neurons. A) current injection protocols for a hyperpolarizing step (left) and a ZAP or chirp current (right, details in the text). B and C, corresponding voltage profiles with I_h blocked, leaving mostly the passive properties of neurons (B) and with I_h active (C). The plots on the right show the impedance amplitude as a function of the frequency (logarithmic scale), obtained from the traces in the middle, for the two conditions. D) The combination of the low-pass filter due to the passive properties of the membrane (grey line) and the high-pass filter imposed by the slow activation of I_h (dotted line) creates a resonance profile, with a peak denoted by the red arrowhead. Note the arrowheads in C) with the same meaning. Modified, with permission, from Hutcheon and Yarom (2000).