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Here, we demonstrate that the transition from early to late adolescence involves extensive reorganization of the retrosplenial (RSP) cortex along with significant memory expression deficits. Specifically, the densities of perineuronal nets (PNNs) and the expression of parvalbumin (PV) established in mice RSP during early adolescence (p30) significantly declined by late adolescence (p60\u2013p75). In parallel, using context fear conditioning, we found that memories acquired during early adolescence were significantly impaired. These cellular and memory changes could be alleviated by PNN stabilization, indicating that they were secondary to PNN loss. Consistent with this, memory expression spontaneously recovered with PNN build-up in later life. Furthermore, late adolescence mice show a decrease in the level of key PNN constituents (especially aggrecan and neurocan) and the expression of transforming growth factor beta (Tgf\u03b2) in RSP. RSP-targeted infusion of Tgf\u03b22 attenuated the decrease of PNN and neurocan, supporting a role of Tgf\u03b22 signaling in PNN build-up. These indicate that the decrease of PNNs during late adolescence was likely due to multiple molecular adaptations. Together, our findings show that RSP ECM undergoes dynamic reorganization until adulthood and beyond, with particularly strong fluctuations during late adolescence. In addition to affecting the expression of remote memories, in susceptible individuals, the observed dynamics could interact with genetic factors, increasing the risk of late adolescent psychopathologies.<\/jats:p>","DOI":"10.1371\/journal.pbio.3003908","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T17:45:12Z","timestamp":1784310312000},"page":"e3003908","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Retrosplenial cortical reorganization during late adolescence introduces instability of contextual memory circuits"],"prefix":"10.1371","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1755-4494","authenticated-orcid":true,"given":"Hui","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zorica","family":"Petrovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth M.","family":"Wood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Cicvaric","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maayan","family":"Krispil-Alon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir","family":"Jovasevic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kendra","family":"Parker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas E.","family":"Bassett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Carboncino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita L.","family":"Guedea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengfei","family":"Yi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gal","family":"Richter-Levin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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