Early deficits in an in vitro striatal microcircuit model carrying the Parkinson’s GBA-N370S mutation
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 pa...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-04-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-024-00694-2 |
| _version_ | 1797209489349279744 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Quyen B. Do |
| collection | DOAJ |
| 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-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. |
| first_indexed | 2024-04-24T09:55:31Z |
| format | Article |
| id | doaj.art-97680562b37f462c955fb032be5c6fe7 |
| institution | Directory Open Access Journal |
| issn | 2373-8057 |
| language | English |
| last_indexed | 2024-04-24T09:55:31Z |
| publishDate | 2024-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj.art-97680562b37f462c955fb032be5c6fe72024-04-14T11:10:50ZengNature Portfolionpj Parkinson's Disease2373-80572024-04-0110111510.1038/s41531-024-00694-2Early deficits in an in vitro striatal microcircuit model carrying the Parkinson’s GBA-N370S mutationQuyen B. Do0Humaira Noor1Ricardo Marquez-Gomez2Kaitlyn M. L. Cramb3Bryan Ng4Ajantha Abbey5Naroa Ibarra-Aizpurua6Maria Claudia Caiazza7Parnaz Sharifi8Charmaine Lang9Dayne Beccano-Kelly10Jimena Baleriola11Nora Bengoa-Vergniory12Richard Wade-Martins13Oxford Parkinson’s Disease Centre and Department of Physiology, Anatomy and Genetics, University of OxfordOxford Parkinson’s Disease Centre and Department of Physiology, Anatomy and Genetics, University of OxfordOxford Parkinson’s Disease Centre and Department of Physiology, Anatomy and Genetics, University of OxfordOxford Parkinson’s Disease Centre and Department of Physiology, Anatomy and Genetics, University of OxfordOxford Parkinson’s Disease Centre and Department of Physiology, Anatomy and Genetics, University of OxfordOxford Parkinson’s Disease Centre and Department of Physiology, Anatomy and Genetics, University of OxfordOxford Parkinson’s Disease Centre and Department of Physiology, Anatomy and Genetics, University of OxfordOxford Parkinson’s Disease Centre and Department of Physiology, Anatomy and Genetics, University of OxfordOxford Parkinson’s Disease Centre and Department of Physiology, Anatomy and Genetics, University of OxfordOxford Parkinson’s Disease Centre and Department of Physiology, Anatomy and Genetics, University of OxfordOxford Parkinson’s Disease Centre and Department of Physiology, Anatomy and Genetics, University of OxfordAchucarro Basque Center for NeuroscienceOxford Parkinson’s Disease Centre and Department of Physiology, Anatomy and Genetics, University of OxfordOxford Parkinson’s Disease Centre and Department of Physiology, Anatomy and Genetics, University of OxfordAbstract 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.https://doi.org/10.1038/s41531-024-00694-2 |
| spellingShingle | 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 Early deficits in an in vitro striatal microcircuit model carrying the Parkinson’s GBA-N370S mutation npj Parkinson's Disease |
| title | Early deficits in an in vitro striatal microcircuit model carrying the Parkinson’s GBA-N370S mutation |
| title_full | Early deficits in an in vitro striatal microcircuit model carrying the Parkinson’s GBA-N370S mutation |
| title_fullStr | Early deficits in an in vitro striatal microcircuit model carrying the Parkinson’s GBA-N370S mutation |
| title_full_unstemmed | Early deficits in an in vitro striatal microcircuit model carrying the Parkinson’s GBA-N370S mutation |
| title_short | Early deficits in an in vitro striatal microcircuit model carrying the Parkinson’s GBA-N370S mutation |
| title_sort | early deficits in an in vitro striatal microcircuit model carrying the parkinson s gba n370s mutation |
| url | https://doi.org/10.1038/s41531-024-00694-2 |
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