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

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.