Early deficits in an in vitro striatal microcircuit model carrying the Parkinson's GBA-N370S mutation

  1. Do, Quyen B. 1234
  2. Noor, Humaira 1245
  3. Marquez Gomez, Ricardo 124
  4. Cramb, Kaithlyn 124
  5. Ng, Brian 1
  6. Abbey, Ajantha 12
  7. Ibarra-Aizpura, Naroa 12
  8. Caiazza, Maria-Claudia 124
  9. Sharifi, Parnaz 12
  10. Lang, Chairmaine 124
  11. Beccano-Kelly, Dayne 12
  12. Baleriola, Jimena 67
  13. Bengoa-Vergniory, Nora 124678
  14. Wade-Martins, Richard 124
  1. 1 Oxford Parkinson's Disease Centre and Department of Physiology, Anatomy and Genetics, University of Oxford, South Park Road, Oxford OX1 3QU, United Kingdom
  2. 2 Kavli Institute for Neuroscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, South Park Road, Oxford OX1 3QU, United Kingdom
  3. 3 Genome Institute of Singapore
    info

    Genome Institute of Singapore

    Singapur, Singapur

    ROR https://ror.org/05k8wg936

  4. 4 Aligning Science Across Parkinson's
  5. 5 Nuffield Department of Medicine (NDM), University of Oxford, Henry Wellcome Building for Molecular Physiology, Old Road, Oxford OX3 7BN, United Kingdom
  6. 6 Ikerbasque
  7. 7 Achucarro Basque Center for Neuroscience
    info

    Achucarro Basque Center for Neuroscience

    Leioa, España

    ROR 00myw9y39

  8. 8 Universidad del País Vasco/Euskal Herriko Unibertsitatea
    info

    Universidad del País Vasco/Euskal Herriko Unibertsitatea

    Lejona, España

    ROR https://ror.org/000xsnr85

Show affiliations +

Editor: Zenodo

Year of publication: 2024

Type: Dataset

CC BY 4.0

DOI: 10.5281/ZENODO.10886973 lock_openOpen access editor

Abstract

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. FILE DESCRIPTIONS Source Data.xlsx: Tabular datasets plotted on main figures 1, 3, 4, 5 and 6. Supplementary Data.xlsx: Tabular datasets plotted on supplementary figures 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, and 12. Key Resources Table.xlsx: Table containing key resources (primary and secondary antibodies, cell lines and software) used in this study. List of Primers.xlsx: Primers used in RT-qPCR.