Abstract
Hyperpolarization–activated cyclic nucleotide–sensitive (HCN) channels mediate the If current in heart and Ih throughout the nervous system. In spiking neurons Ih participates primarily in different forms of rhythmic activity. Little is known, however, about its role in neurons operating with graded potentials as in the retina, where all four channel isoforms are expressed. Intriguing evidence for an involvement of Ih in early visual processing are the side effects reported, in dim light or darkness, by cardiac patients treated with HCN inhibitors. Moreover, electroretinographic recordings indicate that these drugs affect temporal processing in the outer retina. Here we analyzed the functional role of HCN channels in rod bipolar cells (RBCs) of the mouse. Perforated–patch recordings in the dark–adapted slice found that RBCs exhibit Ih, and that this is sensitive to the specific blocker ZD7288. RBC input impedance, explored by sinusoidal frequency–modulated current stimuli (0.1–30 Hz), displays band–pass behavior in the range of Ih activation. Theoretical modeling and pharmacological blockade demonstrate that high–pass filtering of input signals by Ih, in combination with low–pass filtering by passive properties, fully accounts for this frequency–tuning. Correcting for the depolarization introduced by shunting through the pipette–membrane seal, leads to predict that in darkness Ih is tonically active in RBCs and quickens their responses to dim light stimuli. Immunohistochemistry targeting candidate subunit isoforms HCN1–2, in combination with markers of RBCs (PKC) and rod–RBC synaptic contacts (bassoon, mGluR6, Kv1.3), suggests that RBCs express HCN2 on the tip of their dendrites. The functional properties conferred by Ih onto RBCs may contribute to shape the retina's light response and explain the visual side effects of HCN inhibitors.
Highlights
A hyperpolarization–activated current (Ih) with properties similar to cardiac funny current (If, reviewed by [1]) is widely distributed in the brain, as well as in sensory systems
The Ih current expressed by mouse rod bipolar cells (RBCs) appears similar to that previously observed in voltage–clamp protocols in rat slices [19,21,50], a detailed quantitative comparison is hampered by differences in the way the data are collected and presented
Difficult is comparing Ih activation kinetics in RBCs with the wide and partially overlapping ranges found in heterologous expression systems for HCN1 and HCN2 channels [46,51,52]
Summary
A hyperpolarization–activated current (Ih) with properties similar to cardiac funny current (If, reviewed by [1]) is widely distributed in the brain, as well as in sensory systems (see [2]). HCN open in response to membrane hyperpolarization and close upon depolarization but do not inactivate, a property that enables them to contribute as a standing current to neuronal excitability [7,8]. Cytosolic cAMP shifts their range of activation to more depolarized potentials [9] (but see [10]) Their kinetics of activation and deactivation is slow, with time constants up to hundreds of milliseconds or more. Recorded RBCs display Ih, possibly attributable to HCN2 channels that immunolabeling suggests to be expressed at their dendritic tips. In darkness this current is predicted to endow RBCs with frequency–tuning, sharpening the time course of light responses starting from the range of single photon absorption signaling
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