During corticogenesis, cells from the medial ganglionic eminence (MGE) migrate tangentially into the neocortical anlage. Here we report that gamma-aminobutyric acid (GABA), via GABAA receptors, regulates tangential migration. In embryonic telencephalic slices, bicuculline produced an outward current in migrating MGE-derived cells in the neocortex, suggesting the presence of and tonic activation by ambient GABA. Ambient GABA was also present in the MGE, although this required demonstration using as bioassay HEK293 cells expressing high-affinity alpha6/beta2/gamma2s recombinant GABAA receptors. The concentration of ambient GABA was 0.5+/-0.1 microM in both regions. MGE-derived cells before the corticostriate juncture (CSJ) were less responsive to GABA than those in the neocortex, and profiling of GABAA receptor subunit transcripts revealed different expression patterns in the MGE vis-à-vis the neocortex. These findings suggest a dynamic expression of GABAA receptor number or isoform as MGE-derived cells enter the neocortex and become tonically influenced by ambient GABA. Treatment with bicuculline or antibody against GABA did not affect migration of MGE-derived cells before the CSJ but decreased "crossing index," reflecting impeded migration past the CSJ into the neocortex. Treatment with diazepam or addition of exogenous GABA increased crossing index. We conclude that ambient GABA promotes cortical entry of tangentially migrating MGE-derived cells.