NMDA receptors control cortical axonal projections via EPHRIN-B/EPHB signaling

Callosal projections from primary somatosensory cortex (S1) are key for processing somatosensory inputs and integrating sensory-motor information. How the callosal innervation pattern in S1 is formed during early postnatal development is not clear. We found that the normal termination pattern of these callosal projections is disrupted in cortex specific NMDAR mutants. Rather than projecting selectively to the primary/secondary somatosensory cortex (S1/S2) border, axons were uniformly distributed throughout S1. In addition, the density of this projection increased over postnatal life until the mice died by P30. By combining genetic and antibody-mediated loss of function, we demonstrated that it is NR2B-containing NMDA receptors in target S1 that mediate this guidance phenotype, thus playing a central role in interhemispheric connectivity. Furthermore, we found that this function of NMDA receptors in callosal circuit formation is independent of ion channel function and instead depends on interactions with EPHRIN-B/EPHB. Thus, NMDAR cooperates with EPHRIN-B/EPHB in target S1 to control the formation callosal circuits by acting as an accessory axon guidance receptor modulating EPH-dependent repulsion.