Dopaminergic neurons modulate GABA neuron migration in the embryonic midbrain

INTRODUCTION Neuronal migration is a fundamental process in the development of the central nervous system because neurons eventually dwell in regions distinct from their origin. From ventricular zones, neurons and/or neuronal progenitors navigate along diverse courses, radially and tangentially, to their final destination and integrate into specific brain circuits (Corbin et al., 2001; Hatten, 2002; Marín and Rubenstein, 2001; Parnavelas, 2000). A concerted and/or sequentially regulated migration of both excitatory and inhibitory neurons is essential for the emergence of their proper connectivity and brain functions. Unlike in the telencephalon, where neuronal migration has been well elucidated, in the mesencephalon this vital event has been understudied and key factors remain to be defined. Dopaminergic (DA) neurons located in the three anatomically defined areas of the ventral mesencephalon (VM) – the substantia nigra (SN), ventral tegmental area (VTA) and retrorubral field (RRF) – are involved in controlling diverse brain functions, including motor control and cognition, emotion and reward behaviors (Björklund and Dunnett, 2007; Damier et al., 1999; Ding et al., 2011; Lennington et al., 2011; Schultz, 2001; Seeman et al., 1993; Smidt and Burbach, 2007). The migration routes of DA neurons are not well understood and the related literature is contradictory (Hanaway et al., 1971; Kawano et al., 1995), while the route of GABA neurons to the VM is unknown. Here, we study the migratory trajectories of DA and GABA neurons and find that proper migration of GABA neurons to their final location in the VM is dependent on the pre-existing DA neuron palisade. These results provide several new concepts regarding functional interactions between DA and GABA neurons necessary for their proper migration and final connectivity that may translate into novel understanding of potential etiology as well as therapeutic development for many neurological diseases.