Early deficits in an in vitro striatal microcircuit model carrying the Parkinson's GBA-N370S mutation
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 partia...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature
2024
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| _version_ | 1817931167941263360 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Do, QB |
| collection | OXFORD |
| description | 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 | 2024-12-09T03:17:43Z |
| format | Journal article |
| id | oxford-uuid:f31520ce-4f08-463b-862e-a081208da54d |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-12-09T03:17:43Z |
| publishDate | 2024 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:f31520ce-4f08-463b-862e-a081208da54d2024-10-25T14:59:38ZEarly deficits in an in vitro striatal microcircuit model carrying the Parkinson's GBA-N370S mutationJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f31520ce-4f08-463b-862e-a081208da54dEnglishSymplectic ElementsSpringer Nature2024Do, QBNoor, HMarquez-Gomez, RCramb, KMLNg, BAbbey, AIbarra-Aizpurua, NCaiazza, MCSharifi, PLang, CBeccano-Kelly, DBaleriola, JBengoa-Vergniory, NWade-Martins, RUnderstanding 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. |
| spellingShingle | 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 Early deficits in an in vitro striatal microcircuit model carrying the Parkinson's GBA-N370S mutation |
| 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 |
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