Histamine H3 Receptor Antagonists Influence the Directional Growth of Type II Spiral Ganglion Neurites Within the Developing Cochlea of C57BL/6 Mice

Abstract

The histamine H3 receptor (H3R) is a crucial regulator of synaptic plasticity, neurotransmitter release, and neural signaling within the central nervous system. However, its role in the cochlea remains poorly understood, even though mast cells, a rich endogenous source of histamine, have recently been documented in the mammalian cochlea. This study examined H3R expression and localization in the postnatal day 4–5 (P4-5) C57BL/6 mouse cochlea and evaluated its functional consequences under antagonist treatment. RT-qPCR analysis showed significantly higher H3R mRNA levels in the modiolus compared to the organ of Corti and the lateral wall. Immunofluorescence staining confirmed H3R localization in hair cells (HCs) and spiral ganglion neurons (SGNs). Dissected cochlear explants exposed to two distinct H3R antagonists—ciproxifan and pitolisant—at concentrations of 10µM, 50µM, and 100µM, displayed different responses: ciproxifan induced dose-dependent HC loss. In contrast, pitolisant caused no loss of HC but led to stereociliary abnormalities at higher concentrations. Both antagonists disrupted type II SGN neurite projections, redirecting their normal basal-directed trajectory toward the apical region. These findings implicate H3R in maintaining cochlear structural integrity and guiding SGN neurite development during early postnatal maturation. Further investigation into H3R-mediated mechanisms may reveal new therapeutic targets for hearing preservation and repair.