Finally, an interesting observation in this study is that adra2 stimulation affected not only the migratory speed of cortical interneurons but also their directionality. When adra2 agonist was removed from the bath medium, cortical interneurons resumed a normal migratory speed but the directionality of migration was significantly modified in a fraction of cells compared to the control situation. These results suggest that changes in cAMP levels through adra2 stimulation could modify the responsiveness of cortical interneurons to guidance cues. Support for this possibility comes from the observation that

in other systems manipulation of cAMP levels can modify the responsiveness of thalamocortical axons to guidance cues through the monoaminergic activation of G-protein-coupled receptors negatively linked to adenylate cyclase (Bonnin et al., 2007). In this study the effects of adrenergic stimulation Adriamycin on interneuron migration were detected using several different drugs at relatively high concentrations. However, it this website must be noted that in this slice

culture system drugs reached the migrating cells by passively diffusing through the pores of the Millipore inserts. It is thus likely that the cortical interneurons migrating in the slice are exposed to lower drug concentrations. Importantly, application of adra2a/2c agonists significantly decreased the migratory speed of wildtype cortical interneurons compared to adra2a/2c-ko cortical interneurons. These results strongly indicate that the effects of adra2a/2c stimulation on cortical interneurons are dependent on the activation of these receptors. It should be noted, however, that guanfacine slightly affected the migratory speed of GAD65-GFP+ interneurons in adra2a/2c-ko mice, suggesting that this drug could also act independently of adra2a/2c activation. Interestingly, a study using adra2a/2b/2c triple-ko mice has revealed that clonidine, an

adra2 agonist, could modulate heart reactivity by directly acting on HCN (Knaus et al., 2007b). Finally, although adrab1 was found to be expressed in GAD65-GFP+ cells, application of an adrb1 agonist at relatively high concentration failed to modify the migration of interneurons, suggesting that this receptor may not be functional at this embryonic timepoint. In conclusion, we report that several SPTLC1 adrenergic receptors are expressed in migrating cortical interneurons, particularly the adra2a and adra2c subtypes. Using time-lapse imaging we have demonstrated that activation of adra2 affects cortical interneuron migration in a reversible manner. Finally, the distribution of cortical interneurons was altered in vivo in adra2a/2c-ko mice. These results support the hypothesis that adrenergic dysregulation induced by exposure during pregnancy to drugs that block adrenergic receptors may affect cellular processes involved in the assembly of cortical circuits.