Getting connected in the dopamine system

Dopaminergic neurons located in the ventral midbrain (i.e. mesodiencephalic dopamine, mdDA, neurons) are essential for the control of diverse cognitive and motor behaviors and are associated with multiple psychiatric and neurodegenerative disorders. Three anatomically and functionally distinct subgroups of mdDA neurons have been identified (A8-A10) which give rise to prominent forebrain projections (i.e. the mesostriatal, mesocortical and mesolimbic pathways). The development of mdDA neurons is a complex, multi-step process. It includes early developmental events such as cell fate specification, differentiation and migration, and later events including neurite growth, guidance and pruning, and synapse formation. Significant progress has been made in defining the early events involved in mdDA neuron development [see Smits, S.M., Burbach, J.P., Smidt, M.P., 2006. Developmental origin and fate of meso-diencephalic dopamine neurons. Prog. Neurobiol. 78, 1-16.]. Although later stages of mdDA neuron development are less well understood, recent studies have begun to identify cellular and molecular signals thought to be involved in establishing mdDA neuronal connectivity. The purpose of the present review is to summarize our current understanding of the ontogeny and anatomy of mdDA axon pathways, to highlight recent progress in defining the cellular and molecular mechanisms that underlie the formation and remodeling of mdDA circuits, and to discuss the significance of this progress for understanding and treating situations of perturbed connectivity in the mdDA system.