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Here, we developed a custom three-chambered microfluidic platform and established a cortico-striato-nigral microcircuit partially recapitulating the striatal presynaptic landscape in vitro using induced pluripotent stem cell (iPSC)-derived neurons. We found that, cortical glutamatergic projections facilitated MSN synaptic activity, and dopaminergic transmission enhanced maturation of MSNs in vitro. Replacement of wild-type iPSC-derived dopamine neurons (iPSC-DaNs) in the striatal microcircuit with those carrying the PD-related\n                    <jats:italic>GBA-N370S<\/jats:italic>\n                    mutation led to a depolarisation of resting membrane potential and an increase in rheobase in iPSC-MSNs, as well as a reduction in both voltage-gated sodium and potassium currents. Such deficits were resolved in late microcircuit cultures, and could be reversed in younger cultures with antagonism of protein kinase A activity in iPSC-MSNs. Taken together, our results highlight the unique utility of modelling striatal neurons in a modular physiological circuit to reveal mechanistic insights into\n                    <jats:italic>GBA1<\/jats:italic>\n                    mutations in PD.\n                  <\/jats:p>","DOI":"10.1038\/s41531-024-00694-2","type":"journal-article","created":{"date-parts":[[2024,4,12]],"date-time":"2024-04-12T04:01:48Z","timestamp":1712894508000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Early deficits in an in vitro striatal microcircuit model carrying the Parkinson\u2019s GBA-N370S mutation"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4223-0886","authenticated-orcid":false,"given":"Quyen B.","family":"Do","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Humaira","family":"Noor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5810-2670","authenticated-orcid":false,"given":"Ricardo","family":"Marquez-Gomez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2822-7752","authenticated-orcid":false,"given":"Kaitlyn M. 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