| Autor: |
Quyen B. Do, Humaira Noor, Ricardo Marquez-Gomez, Kaitlyn M. L. Cramb, Bryan Ng, Ajantha Abbey, Naroa Ibarra-Aizpurua, Maria Claudia Caiazza, Parnaz Sharifi, Charmaine Lang, Dayne Beccano-Kelly, Jimena Baleriola, Nora Bengoa-Vergniory, Richard Wade-Martins |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
npj Parkinson's Disease, Vol 10, Iss 1, Pp 1-15 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2373-8057 |
| DOI: |
10.1038/s41531-024-00694-2 |
| Popis: |
Abstract Understanding medium spiny neuron (MSN) physiology is essential to understand motor impairments in Parkinson’s disease (PD) given the architecture of the basal ganglia. 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 GBA-N370S 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 GBA1 mutations in PD. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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