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

Editor: Zenodo

Año de publicación: 2024

Tipo: Dataset

Resumen

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.