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

Do, Q. B.; Ng, B.; Marquez-Gomez, R.; Beccano-Kelly, D.; Ibarra-Aizpurua, N.; Caiazza, M.-C.; Lang, C.; Baleriola, J.; Bengoa-Vergniory, N.; Wade-Martins, R.

doi:10.1101/2023.03.01.530566

bioRxiv · 10.1101/2023.03.01.530566

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

Do, Q. B.·Ng, B.·Marquez-Gomez, R.·Beccano-Kelly, D.·Ibarra-Aizpurua, N.·Caiazza, M.-C.·Lang, C.·Baleriola, J.·Bengoa-Vergniory, N.·Wade-Martins, R.

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Abstract

Understanding medium spiny neuron (MSN) physiology is essential to understand motor impairments in Parkinsons 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.

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Do, Q. B., Ng, B., Marquez-Gomez, R., Beccano-Kelly, D., Ibarra-Aizpurua, N., Caiazza, M.-C., Lang, C., Baleriola, J., Bengoa-Vergniory, N., Wade-Martins, R.. 2023-03-02. Early striatal hyperexcitability in an in vitro human striatal microcircuit model carrying the Parkinson's GBA-N370S mutation. https://doi.org/10.1101/2023.03.01.530566

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