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Perineuronal nets (PNNs) significantly restrict synaptic plasticity by inhibiting synapse formation. The digestion of PNNs has been associated with short-term cognitive improvements and reduced long-term memory, offering potential therapeutic benefits in PTSD. This study investigates the correlation between PNNs and fear memory processes in extracellular matrix (ECM) mutant mice, particularly focusing on the amygdala-medial prefrontal cortex (mPFC) circuit, which is crucial for fear memory generation and maintenance. Fear conditioning was conducted on mice lacking four key ECM-molecules: brevican, neurocan, tenascin-C and tenascin-R (4x KO). These mice exhibited severe impairments in memory consolidation, as evident by their inability to retrieve previously learned fear memories, coupled with reduced PNN density and disturbed synaptic integrity along their PNNs. Additionally, changes in neural activity in the basolateral amygdala (BL) and reductions in VGAT\n                    <jats:sup>+<\/jats:sup>\n                    synaptic puncta in the amygdala-mPFC circuit were observed. In contrast, tenascin single KOs showed intact fear behavior and memory compared to their control groups. Impaired fear memory consolidation can be advantageous in certain conditions, such as PTSD, making the 4x KO mice an intriguing model for future fear conditioning studies and highlighting brevican, neurocan, Tnc, and Tnr as compelling targets for further investigation. This study underscores the significance of ECM regulation for synaptic organization and the potential of PNN modulation as a therapeutic target for fear memory-related conditions.\n                  <\/jats:p>","DOI":"10.1038\/s41598-025-89580-2","type":"journal-article","created":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T13:10:02Z","timestamp":1739538602000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Combined loss of brevican, neurocan, tenascin-C and tenascin-R leads to impaired fear retrieval due to perineuronal net loss"],"prefix":"10.1038","volume":"15","author":[{"given":"Cornelius","family":"Mueller-Buehl","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Pakusch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verian","family":"Bader","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstanze F.","family":"Winklhofer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie D.","family":"Mark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Faissner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,14]]},"reference":[{"issue":"2","key":"89580_CR1","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/S2215-0366(21)00395-3","volume":"9","author":"Global Burden of Disease 2019 Mental Disorder Collaborators","year":"2022","unstructured":"Global Burden of Disease 2019 Mental Disorder Collaborators. 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