Heterogeneity of dopamine release sites in health and degeneration

Despite comprising only ~ 0.001% of all neurons in the human brain, ventral midbrain dopamine neurons exert a profound influence on human behavior and cognition. As a neuromodulator, dopamine selectively inhibits or enhances synaptic signaling to coordinate neural output for action, attention, and affect. Humans invariably lose brain dopamine during aging, and this can be exacerbated in disease states such as Parkinson's Disease. Further, it is well established in multiple disease states that cell loss is selective for a subset of highly sensitive neurons within the nigrostriatal dopamine tract. Regional differences in dopamine tone are regulated pre-synaptically, with subcircuits of projecting dopamine neurons exhibiting distinct molecular and physiological signatures. Specifically, proteins at dopamine release sites that synthesize and package cytosolic dopamine, modulate its release and reuptake, and alter neuronal excitability show regional differences that provide linkages to the observed sensitivity to neurodegeneration. The aim of this review is to outline the major components of dopamine homeostasis at neurotransmitter release sites and describe the regional differences most relevant to understanding why some, but not all, dopamine neurons exhibit heightened vulnerability to neurodegeneration.