Vulnerability of different dopaminergic neurons within the midbrain to alpha-synuclein aggregates

Alpha synuclein (alpha-syn) is an endogenous intracellular protein found within a subset of neurons predominantly at their presynaptic terminals. Aggregation of alpha-syn molecules to form oligomers causes neural dysfunction during ageing, particularly in a group of neurons that release the catecholamine neurotransmitter dopamine. These neurons are involved in a wide range of complex behaviours, such as motor control, motivation, reward, attention, and memory. Dopaminergic cell bodies are mostly located within the substantia nigra pars compacta (SNc) and in the ventral tegmental area (VTA) within the midbrain. Hill et al (2021) demonstrated that alpha- syn aggregates introduced into SNc dopamine neurons reduce their firing rate and decrease their input resistance. These effects could be reversed by blocking a specific K+ channel (KATP). It is hypothesised that it is the expression of this KATP channel in SNc dopamine neurons that makes them susceptible to the effects of alpha-syn oligomers, that accumulate during aging. This hypothesis will be investigated by comparing the actions of alpha-syn oligomers on susceptible (SNc) and resistant (VTA) dopaminergic neurons using whole cell patch clamp recording. Electrophysiological properties will be measured using standard step IV curves and using the dynamic IV method (Hill et al 2021). Fast scan voltammetry will be used to measure dopamine release as a functional read out of dopamine cell function. Single cell RT-PCR will be used to measure KATP expression. Mathematical modelling will be used to simulate the electrophysiological properties of the dopamine neurons and explore the effects that alpha-syn oligomers have on neural circuit function.