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The molecular mechanisms contributing to the formation, as well as interplay between the pre- and postsynaptic components, remain largely unclear. Here, we tested the role of the synaptic adhesion molecule and Nogo\/RTN4 receptor homolog RTN4RL2 (also referred to as NgR2) in the development and function of afferent IHC\u2013SGN synapses. Upon deletion of RTN4RL2 in mice (RTN4RL2 KO), presynaptic IHC active zones showed enlarged synaptic ribbons and a depolarized shift in the activation of Ca\n                    <jats:sub>V<\/jats:sub>\n                    1.3 Ca\n                    <jats:sup>2+<\/jats:sup>\n                    channels. The postsynaptic densities (PSDs) of SGNs were smaller and deficient of GluA2\u20134 AMPA receptor subunits despite maintained\n                    <jats:italic>Gria2<\/jats:italic>\n                    mRNA expression in SGNs. Next to synaptically engaged PSDs, we observed \u2018orphan\u2019 PSDs located away from IHCs, likely belonging to a subset of SGN peripheral neurites that do not contact the IHCs in RTN4RL2 KO cochleae, as found by volume electron microscopy reconstruction of SGN neurites. Auditory brainstem responses of RTN4RL2 KO mice showed increased sound thresholds indicating impaired hearing. Together, these findings suggest that RTN4RL2 contributes to the proper formation and function of auditory afferent synapses and is critical for normal hearing.\n                  <\/jats:p>","DOI":"10.7554\/elife.103481","type":"journal-article","created":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T10:25:06Z","timestamp":1739355906000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.103481","source":"Crossref","is-referenced-by-count":1,"title":["Probing the role of synaptic adhesion molecule RTN4RL2 in setting up cochlear connectivity"],"prefix":"10.7554","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-3999-2427","authenticated-orcid":true,"given":"Nare","family":"Karagulyan","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/021ft0n22","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute for Auditory Neuroscience, University Medical Center G\u00f6ttingen","place":["G\u00f6ttingen, 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