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PNNs are condensed aggregates of extracellular matrix molecules surrounding specific types of neurons, which regulate neuroplasticity and memory. However, the role of PNN-associated Sema3A in these processes remains unclear. To address this topic, we investigated the contribution of Sema3A to cerebellum-dependent learning and memory in adult mice using the eyeblink conditioning (EBC) paradigm. We interfered with Sema3A signalling by employing: (i) a molecular approach, in which secreted Sema3A receptors (neuropilin-1 bodies) were expressed in the anterior interposed nuclei (AIN) via viral vector injection; and (ii) a genetic approach, using mutant mice with impaired Sema3A signalling (K108N mice). Mice expressing neuropilin-1 bodies showed reduced EBC performance at the beginning of the memory retention phase. However, increased inflammation was found in the AIN of these mice, challenging the interpretation of these findings. K108N mice showed enhanced EBC performance at the beginning of the memory retention phase. No synaptic structural changes were detected in the AIN of K108N mice at the end of the EBC paradigm. Based on our findings in K108N mice, constitutively altered Sema3A signalling is associated with subtle improvement in cerebellar memory.<\/jats:p>","DOI":"10.3390\/ijms27125304","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T06:53:10Z","timestamp":1781247190000},"page":"5304","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Impact of Sema3A Interference on Cerebellum-Dependent Motor Associative Learning and Memory"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2838-8708","authenticated-orcid":false,"given":"Geoffrey-Alexander","family":"Gimenez","sequence":"first","affiliation":[{"name":"Department of Neuroregeneration, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands"},{"name":"Department of Cerebellar Coordination & Cognition, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Van Der Zwaag","sequence":"additional","affiliation":[{"name":"Department of Cerebellar Coordination & Cognition, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5961-3209","authenticated-orcid":false,"given":"Cynthia M.","family":"Geelen","sequence":"additional","affiliation":[{"name":"Department of Cerebellar Coordination & Cognition, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5847-8173","authenticated-orcid":false,"given":"Melissa","family":"Van Hemert","sequence":"additional","affiliation":[{"name":"Department of Cerebellar Coordination & Cognition, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jop","family":"Vreeken","sequence":"additional","affiliation":[{"name":"Department of Cerebellar Coordination & Cognition, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3042-2429","authenticated-orcid":false,"given":"Fred","family":"de Winter","sequence":"additional","affiliation":[{"name":"Department of Neuroregeneration, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9594-1564","authenticated-orcid":false,"given":"Cathrin B.","family":"Canto","sequence":"additional","affiliation":[{"name":"Department of Cerebellar Coordination & Cognition, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1365-7063","authenticated-orcid":false,"given":"Daniela","family":"Carulli","sequence":"additional","affiliation":[{"name":"Department of Neuroregeneration, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris I.","family":"De Zeeuw","sequence":"additional","affiliation":[{"name":"Department of Cerebellar Coordination & Cognition, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands"},{"name":"Department of Neuroscience, Erasmus MC, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joost","family":"Verhaagen","sequence":"additional","affiliation":[{"name":"Department of Neuroregeneration, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands"},{"name":"Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The 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