Adenosine A(2A) Receptors Contribute to the Radial Migration of Cortical Projection Neurons through the Regulation of Neuronal Polarization and Axon Formation

Cortical interneurons born in the subpallium reach the cortex through tangential migration, whereas pyramidal cells reach their final position by radial migration. Purinergic signaling via P2Y1 receptors controls the migration of intermediate precursor cells from the ventricular zone to the subventricular zone. It was also reported that the blockade of A(2A) receptors (A(2A)R) controls the tangential migration of somatostatin(+) interneurons. Here we found that A(2A)R control radial migration of cortical projection neurons. In A(2A)R-knockout (KO) mouse embryos or naive mouse embryos exposed to an A(2A)R antagonist, we observed an accumulation of early-born migrating neurons in the lower intermediate zone at late embryogenesis. In utero knockdown of A(2A)R also caused an accumulation of neurons at the lower intermediate zone before birth. This entails the presently identified ability of A(2A)R to promote multipolar-bipolar transition and axon formation, critical for the transition of migrating neurons from the intermediate zone to the cortical plate. This effect seems to require extracellular ATP-derived adenosine since a similar accumulation of neurons at the lower intermediate zone was observed in mice lacking ecto-5 '-nucleotidase (CD73-KO). These findings frame adenosine as a fine-tune regulator of the wiring of cortical inhibitory and excitatory networks.