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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\u20135 (P4-5) C57BL\/6 mouse cochlea and evaluated its functional consequences under antagonist treatment. RT-qPCR analysis showed significantly higher <jats:italic>H3R<\/jats:italic> 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\u2014ciproxifan and pitolisant\u2014at concentrations of 10\u00b5M, 50\u00b5M, and 100\u00b5M, 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.<\/jats:p>","DOI":"10.1007\/s11064-025-04521-9","type":"journal-article","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T10:19:22Z","timestamp":1755080362000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Histamine H3 Receptor Antagonists Influence the Directional Growth of Type II Spiral Ganglion Neurites Within the Developing Cochlea of C57BL\/6 Mice"],"prefix":"10.1007","volume":"50","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5398-0327","authenticated-orcid":false,"given":"Lingyi","family":"Kong","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9987-6392","authenticated-orcid":false,"given":"Heidi","family":"Olze","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9292-6606","authenticated-orcid":false,"given":"Agnieszka J.","family":"Szczepek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,8,13]]},"reference":[{"key":"4521_CR1","doi-asserted-by":"publisher","first-page":"3354","DOI":"10.1016\/j.febslet.2015.08.030","volume":"589","author":"JD Goutman","year":"2015","unstructured":"Goutman JD, Elgoyhen AB, G\u00f3mez-Casati ME (2015) Cochlear hair cells: the sound-sensing machines. 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