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Calcium-dependent synaptic and structural plasticity mechanisms were incorporated, allowing neural activity to alter network topology. We show how hyperactivity of indirect pathway striatal projection neurons (iMSN) can induce synaptic connectivity changes consistent with PD animal models. Our results suggest that synaptic reorganization following DD results from a series of homeostatic calcium\u2013based synaptic changes triggered by iMSN hyperactivity. While this structural plasticity functions as a compensatory mechanism in the cascade of changes following elevated iMSN input from striatal DD, it may become compromised if iMSN and cortical inputs show substantial bursting activity.<\/jats:p>","DOI":"10.1126\/sciadv.adw7421","type":"journal-article","created":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T18:58:33Z","timestamp":1762541913000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":3,"title":["Calcium-based synaptic and structural plasticity link pathological activity to synaptic reorganization in Parkinson\u2019s disease"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9086-6286","authenticated-orcid":true,"given":"Cathal","family":"McLoughlin","sequence":"first","affiliation":[{"name":"Department of Electrical and Electronic Engineering, University College Dublin, Dublin D04 V1W8, Ireland."},{"name":"Department of Neurosurgery, Stanford University, Stanford, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justus A.","family":"Kromer","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Stanford University, Stanford, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6743-360X","authenticated-orcid":true,"given":"Madeleine","family":"Lowery","sequence":"additional","affiliation":[{"name":"Department of Electrical and Electronic Engineering, University College Dublin, Dublin D04 V1W8, Ireland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5736-7415","authenticated-orcid":true,"given":"Peter A.","family":"Tass","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Stanford University, Stanford, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.13691"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.13"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.baga.2014.11.001"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/0166-2236(89)90074-X"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/0166-2236(90)90110-V"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0090-6"},{"key":"e_1_3_2_8_2","unstructured":"C. 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