Differential effects of α-synuclein aggregates on the electrophysiology of SNpc vs VTA dopaminergic neurons in acute mouse slices

Parkinson’s disease (PD) is characterised by the early loss of dopaminergic neurons (DNs) in substantia nigra pars compacta (SNpc) with other DNs more resistant. Aggregation of alpha synuclein (α-Syn) appears to be a major driver of pathology. We have investigated the differential effects of intracellular α-Syn aggregates on the electrophysiology of SNpc and VTA DNs in acute slices. Introduction of α-Syn aggregates into single SNpc DNs increased whole-cell conductance and altered firing, effects partially reversed by the K ATP channel inhibitor glibenclamide. These effects were either absent or much weaker in VTA DNs. Although diazoxide (K ATP channel opener) had little effect on VTA DNs compared to SNpc, the effects were significantly enhanced by α-Syn aggregates. These findings demonstrate that acute introduction of α-Syn aggregates significantly changes the electrophysiological properties of SNpc DNs, which is mediated in part by the presence of K ATP channels, with these effects much reduced in VTA DNs.