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The cytoplasmic, carboxy-terminal domain (CTD) is highly sequence-divergent across AMPAR subunits, and has received considerable attention for its role during long-term potentiation (LTP) at CA1 pyramidal neuron synapses. However, its function at other synapses and, more broadly, its contribution to different GluA1-dependent processes, is poorly understood. Here, we used mice with a constitutive truncation of the GluA1 CTD to dissect its role regulating AMPAR localization and function as well as its contribution to cognitive and affective processes. We found that GluA1 CTD truncation affected AMPAR subunit levels and intracellular trafficking. \u0394CTD GluA1 mice exhibited no memory deficits, but presented exacerbated novelty-induced hyperlocomotion and dentate gyrus granule cell (DG GC) hyperactivity, as well as other behavioral alterations. Mechanistically, we found that AMPAR EPSCs onto DG GABAergic interneurons were significantly reduced, presumably underlying, at least in part, the observed changes in neuronal activity and behavior. In summary, this study dissociates CTD-dependent from CTD-independent GluA1 functions, unveiling the GluA1 CTD as a crucial hub regulating AMPAR function in a cell type-specific manner.<\/jats:p>","DOI":"10.1038\/s41380-025-03328-y","type":"journal-article","created":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T12:52:53Z","timestamp":1763815973000},"page":"2119-2132","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The GluA1 cytoplasmic tail regulates intracellular AMPA receptor trafficking and synaptic transmission onto dentate gyrus GABAergic interneurons, gating response to novelty"],"prefix":"10.1038","volume":"31","author":[{"given":"Gerardo","family":"Leana-Sandoval","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis","family":"Madrid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ananth V.","family":"Kolli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlene A.","family":"Chinn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6790-3604","authenticated-orcid":false,"given":"Matthew A.","family":"Sandoval","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris","family":"Lo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Alizo Vera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Simms","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2029-4176","authenticated-orcid":false,"given":"Marcelo A.","family":"Wood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4980-7441","authenticated-orcid":false,"given":"Javier","family":"D\u00edaz-Alonso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,22]]},"reference":[{"key":"3328_CR1","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1016\/0896-6273(88)90148-1","volume":"1","author":"JA Kauer","year":"1988","unstructured":"Kauer JA, Malenka RC, Nicoll RA. 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