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Hearing loss is widely viewed as a modifiable risk factor for Alzheimer's disease (AD). During normal aging the inferior colliculus (IC), a large auditory midbrain nucleus, undergoes numerous changes to neurotransmission, and these changes contribute to the development of central gain and presbycusis. Recent reports also implicate the IC as a nucleus that undergoes processing changes during AD. We used transmission electron microscopy (EM) to examine the synaptic ultrastructure of the central IC (ICc) in 3xTG mice during presymptomatic, emerging, and established disease stages. Synapses were identified by a collection of presynaptic vesicles, a clear synaptic cleft, and a postsynaptic density. Symmetric synapses had pre and postsynaptic membranes of similar thickness, whereas asymmetric synapses had postsynaptic densities were conspicuously thicker than the presynaptic densities. We also quantified the presynaptic profile areas, active zone lengths, and presynaptic mitochondria. The data demonstrate a significant loss of symmetric and asymmetric synapses in the emerging disease stage. In particular, the density of symmetric synapses in the ICc was reduced by \u223c50%. As inhibitory neurotransmitters gamma\u2010aminobutyric acid (GABA), glycine, and neuropeptide Y are released from neurons that form symmetric synapses in the IC, the robust loss of these synapses may contribute to central gain and presbycusis during AD. Furthermore, as these synapses were lost well before the established disease stages, perhaps alterations in ICc represent an early biomarker for Alzheimer's progression.<\/jats:p>","DOI":"10.1002\/cne.70120","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T16:55:32Z","timestamp":1765817732000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Ultrastructural Synaptic Differences in the Central Inferior Colliculus in the 3xTG Mouse Across Three Disease Stages"],"prefix":"10.1002","volume":"533","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4753-7326","authenticated-orcid":false,"given":"Jeffrey G.","family":"Mellott","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences Northeast Ohio Medical University  Rootstown Ohio USA"},{"name":"University Hospitals Hearing Research Center Northeast Ohio Medical University  Rootstown Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lena M.","family":"Dellaria","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences Northeast Ohio Medical University  Rootstown Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madeline","family":"Guy","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences Northeast Ohio Medical University  Rootstown Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2235-5613","authenticated-orcid":false,"given":"Sean R.","family":"Hergenrother","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences Northeast Ohio Medical University  Rootstown Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nick J.","family":"Tokar","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences Northeast Ohio Medical University  Rootstown Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dakota Z.","family":"Smallridge","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences Northeast Ohio Medical University  Rootstown Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miljan","family":"Terzic","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences Northeast Ohio Medical University  Rootstown Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jesse W.","family":"Young","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences Northeast Ohio Medical University  Rootstown Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine M.","family":"Dengler\u2010Crish","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences Northeast Ohio Medical University  Rootstown Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,12,15]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2025.1626021"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.npep.2025.102566"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncir.2022.871924"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2018.09.036"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2014.00206"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0306\u20104522(00)00340\u20107"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v067.i01"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0406\u201018.2018"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0217\u201016.2016"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12873"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.2517-6161.1995.tb02031.x"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2005.01.040"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-06-02383.2002"},{"key":"e_1_2_11_15_1","first-page":"69","volume-title":"The Inferior Colliculus","author":"Cant N. 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