Early deficits in an in vitro striatal microcircuit model carrying the Parkinson's GBA-N370S mutation
Summary
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. © 2024. The Author(s).
| Authors | Do QB, Noor H, Marquez-Gomez R, Cramb KML, Ng B, Abbey A, Ibarra-Aizpurua N, Caiazza MC, Sharifi P, Lang C, Beccano-Kelly D, Baleriola J, Bengoa-Vergniory N, Wade-Martins R |
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| Journal | NPJ Parkinson's disease |
| Publication Date | 2024 Apr 12;10(1):82 |
| PubMed | 38609392 |
| PubMed Central | PMC11014935 |
| DOI | 10.1038/s41531-024-00694-2 |