Expression and function of HCN channels in ON-bipolar cells: preserved mechanisms for membrane repolarization in retinal degeneration

Jung Woong Chu1,2,*, Bokeum Kang1,*, Kyungmin Kim1 , Hyeonhee Roh1 , Yong Soo Park3 , Min Soo Kim1,2 , Seok-Kyu Kwon1,2, Maesoon Im1,2,4 , Uhtaek Oh1,5 , Gyu-Sang Hong1,2,5

ABSTRACT

PURPOSE. Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels regulate

cardiac and central nervous system neuronal excitability. However, their roles in ON-bipolar

cells, particularly HCN2 and HCN4, remain understudied. This study examines the expression

and function of HCN channels in wild-type (WT) and rd10 mouse retinas, a model of retinal

degeneration.

METHODS. Fluorescence in situ hybridization with subtype-specific markers was used to

assess HCN channel expression in ON-bipolar cells. Whole-cell patch-clamp recordings

measured hyperpolarization-activated currents (Ih) in WT and rd10 retinas. Pharmacological

blockade of HCN channels was applied to evaluate its effects on membrane repolarization.

RESULTS. Despite significant photoreceptor loss, HCN channels were broadly expressed

across multiple ON-bipolar cell types and remained preserved in rd10 mice. Electrophysiology

confirmed robust Ih currents with comparable amplitudes and activation kinetics in WT and

rd10 retinas. Blocking HCN channels in ON-bipolar cells delayed membrane repolarization

following hyperpolarization.

CONCLUSIONS. Our findings highlight that HCNs are essential for dark adaptation in ON-

bipolar cells. HCNs’ expression and function were retained in retinal degeneration, suggesting

a potential therapeutic target for preserving inner retinal function in degenerative diseases.