Distinct requirements for Ascl1 in subpopulations of midbrain GABAergic neurons

Midbrain GABAergic neurons regulate multiple aspects of behavior and play important roles in psychiatric and neurological disease. These neurons constitute several anatomical and functional subpopulations, but their molecular heterogeneity and developmental regulatory mechanisms are poorly understood. Here we have studied the involvement of the proneural gene Ascl1 in the development of the midbrain GABAergic neurons. Analysis of Ascl1 mutant mice demonstrated highly region-specific requirements for Ascl1 for development of different GABAergic neuron subpopulations. Ascl1 is dispensable for the development of the ventral-most midbrain GABAergic neurons associated with dopaminergic nuclei substantia nigra pars reticulata (SNpr) and ventral tegmental area (VTA) GABAergic neurons. In the ventrolateral midbrain, loss of Ascl1 results in markedly delayed neurogenesis in the midbrain domains m3-m5. Within this region, Ascl1 has a unique role in m4, where it also regulates glutamatergic neurogenesis. Our results suggest that the m3-m5 midbrain neuroepithelium gives rise to the GABAergic neuron groups located in the midbrain reticular formation and ventrolateral periaqueductal gray. In contrast to m3-m5, Ascl1 is absolutely required in the dorsal midbrain domains m1-m2, for generation of the GABAergic neurons populating the superior and inferior colliculi as well as dorsal periaqueductal gray. These studies demonstrate different molecular regulatory mechanisms for the distinct midbrain GABAergic neuron subpopulations. Also, our results have implications on understanding the origins of the various midbrain GABAergic neuron groups in the embryonic neuroepithelium.