A comprehensive review of HCN channel expression and Ih in the auditory system: Then, now, and future perspectives.

Abstract

The hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channel is highly specialized, mediating the flow of potassium and sodium ions when a cell is hyperpolarized. Since it was discovered nearly half a century ago, the HCN channel structure and function have been extensively characterized throughout the nervous system. This includes the auditory system, where HCN channels are abundantly expressed and are utilized to encode sound features with high temporal fidelity. Despite the ubiquitous presence of HCN channels in auditory regions, the physiological benefits of these channels within the auditory system have not been synthesized. Here, we summarize the reported empirical measurements of HCN channel expression and HCN channel-mediated current, known as I_h. From the hair cells of the inner ear to the auditory cortex, this comprehensive review reveals HCN channel contributions that mediate sound encoding (Graphical Abstract). First, HCN channel subtype expression is heterogeneous and varies along the auditory structures' frequency axis (i.e., tonotopic gradient). Second, I_h contributes to action potential firing patterns and is influenced by channel localization, metabolic rate, and cyclic nucleotides in a context-dependent manner. Finally, HCN channels promote behaviors related to auditory perception, including synaptic coincidence detection, a property critical for auditory temporal processing, sound localization, and binaural hearing. This review establishes key features of HCN channels and I_h, highlighting seminal work, emerging trends, and gaps in knowledge for future research.