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Published February 12, 2024 | Version v2
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Early striatal hyperexcitability in an in vitro human striatal microcircuit model carrying the Parkinson's GBA-N370S mutation

Authors/Creators

  • 1. Oxford Parkinson's Disease Centre and Department of Physiology, Anatomy and Genetics, University of Oxford, South Park Road, Oxford OX1 3QU, United Kingdom; Kavli Institute for Neuroscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, South Park Road, Oxford OX1 3QU, United Kingdom; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA
  • 2. Oxford Parkinson's Disease Centre and Department of Physiology, Anatomy and Genetics, University of Oxford, South Park Road, Oxford OX1 3QU, United Kingdom; Kavli Institute for Neuroscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, South Park Road, Oxford OX1 3QU, United Kingdom
  • 3. Achucarro Basque Center for Neuroscience, Leioa, Spain; Ikerbasque - Basque Foundation for Science, Bilbao, Spain
  • 4. Oxford Parkinson's Disease Centre and Department of Physiology, Anatomy and Genetics, University of Oxford, South Park Road, Oxford OX1 3QU, United Kingdom; Kavli Institute for Neuroscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, South Park Road, Oxford OX1 3QU, United Kingdom; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA; Achucarro Basque Center for Neuroscience, Leioa, Spain; Ikerbasque - Basque Foundation for Science, Bilbao, Spain; Ikerbasque - Basque Foundation for Science, Bilbao, Spain

Description

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-chamber microfluidic platform and established a cortico-striato-nigral microcircuit recapitulating the striatal presynaptic triad in vitro using induced pluripotent stem cell (iPSC)-derived neurons. We found that, although cortical glutamatergic projections facilitated MSN synaptic activity, dopaminergic transmission was essential for excitability maturation of MSNs in vitro. Replacement of wild-type iPSC-dopamine neurons (iPSC-DaNs) in the striatal microcircuit with those carrying the PD-related GBA-N370S mutation induced early hyperexcitability in iPSC-MSNs through reduction of voltage-gated sodium and potassium intrinsic currents. Such deficits were resolved in aged cultures or with antagonism of protein kinase A activity in nigrostriatal iPSC-DaNs. Hence, our results highlight the unique utility of modelling striatal neurons in a modular and highly physiological circuit which is essential to reveal mechanistic insights of the loss of electrical functional integrity in the striata of GBA1 PD patients.

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.

Files

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Additional details

Related works

Is cited by
Preprint: 10.1101/2023.03.01.530566v1 (DOI)

Funding

Aligning Science Across Parkinson's
Mapping the modulatory landscape governing striatal dopamine signaling and its dysregulation in Parkinson’s disease ASAP-020370

References