The integration of interneuron subtypes into specific microcircuits is essential for proper cortical function. Understanding to what extent interneuron diversity is regulated and maintained during development might help to reveal the principles that govern their role as synchronizing elements as well as causes for dysfunction. Particular interneuron subtypes are generated in a temporally regulated manner in the medial ganglionic eminence (MGE), the caudal ganglionic eminence, and the preoptic area (POA) of the basal telencephalon. Long-range tangential migration from their site of origin to cortical targets is orchestrated by a variety of attractive, repulsive, membrane-bound, and secreted signaling molecules, to establish the critical balance of inhibition and excitation. It remains unknown whether interneurons deriving from distinct domains are predetermined to migrate in particular routes and whether this process underlies cell type-specific regulation. We found that POA-and MGE-derived cortical interneurons migrate within spatially segregated corridors. EphrinB3, expressed in POA-derived interneurons traversing the superficial route, acts as a repellent signal for deeply migrating interneurons born in the MGE, which is mediated by EphA4 forward signaling. In contrast, EphA4 induces repulsive ephrinB3 reverse signaling in interneurons generated in the POA, restricting this population to the superficial path. Perturbation of this bidirectional ephrinB3/EphA4 signaling in vitro and in vivo leads to a partial intermingling of cells in these segregated migratory pathways. Thus, we conclude that cell contact-mediated bidirectional ephrinB3/EphA4 signaling mediates the sorting of MGE-and POA-derived interneurons in the deep and superficial migratory stream.

Cortical interneurons are born in the proliferative zones of the ganglionic eminences in the subpallium and migrate to the developing cortex along well-defined tangential routes. The mechanisms regulating interneuron migration are not completely understood. Here we examine the role of class-A members of the Eph/ephrin system in directing the migration of interneurons. In situ hybridizations demonstrated that ephrin-A3 is expressed in the developing striatum, an area that is strictly avoided by migrating cortical interneurons in vivo, which express the EphA4 receptor. We then examined interneuron migration in grafting experiments, where explants of the medial ganglionic eminence (MGE) from enhanced green fluorescent protein-expressing transgenic mice were homotopically grafted into host slices from wildtype littermate embryos. After blocking ephrin-A ligands, many interneurons invaded the striatal anlage. Moreover, stripe assay experiments revealed that ephrin-A3 acts as a repellent cue for neurons from the medial ganglionic eminence. Downregulation of the EphA4 receptor via siRNA transfection reduced the repulsive effect of ephrin-A3, indicating that EphA4 mediates at least in part the repulsive effect of ephrin-A3 on these cells. Together, these results suggest that ephrin-A3 acts as a repulsive cue that restricts cortical interneurons from entering inappropriate regions and thus contributes to define the migratory route of cortical interneurons.

Inhibitory interneurons comprise only about 20% of cortical neurons and thus constitute a clear minority compared to the vast number of excitatory projection neurons. They are, however, an influential minority with important roles in cortical maturation, function, and plasticity. In this paper, we will highlight the functional importance of cortical inhibition throughout brain development, starting with the embryonal formation of the cortex, proceeding by the regulation of sensory cortical plasticity in adulthood, and finishing with the GABA involvement in sensory information processing in old age.

Disrupted-in-Schizophrenia 1 (DISC1) is a prominent susceptibility gene for major psychiatric disorders. Previous work indicated that DISC1 plays an important role during neuronal proliferation and differentiation in the cerebral cortex and that it affects the positioning of radial migrating pyramidal neurons. Here we show that in mice, DISC1 is necessary for the migration of the cortical interneurons generated in the medial ganglionic eminence (MGE). RT-PCR, in situ hybridizations, and immunocytochemical data revealed expression of DISC1 transcripts and protein in MGE-derived cells. To study the possible functional role of DISC1 during tangential migration, we performed in utero and ex utero electroporation to suppress DISC1 in the MGE in vivo and in vitro. Results indicate that after DISC1 knockdown, the proportion of tangentially migrating MGE neurons that reached their cortical target was strongly reduced. In addition, there were profound alterations in the morphology of DISC1-deficient neurons, which exhibited longer and less branched leading processes than control cells. These findings provide a possible link between clinical studies reporting alterations of cortical interneurons in schizophrenic patients and the current notion of schizophrenia as a neurodevelopmental disorder.

Chondroitin sulfate (CS) carrying proteoglycans (PGs) are widely expressed in the nervous system, and there is increasing evidence that they regulate developmental mechanisms like neurite outgrowth, axonal guidance and neuronal migration. Moreover, they can also act indirectly by organizing and/or modulating growth factors and guidance molecules. We found that chondroitin-4-sulfate is coexpressed with semaphorin 3A (Sema 3A) in the striatal mantle zone (SMZ), a nontarget region of neuropilin (Nrp)-1-expressing cortical interneurons flanking their migratory route in the subpallium. Using in vitro assays, we showed that CS PGs exert a repulsive effect on cortical interneurons, independently of Sema 3A, due to the CS side chains. We further showed that extracellular Sema 3A binds to CS. Disrupting Sema 3A-Nrp-1 signaling led migrating medial ganglionic eminence neurons to inappropriately invade the SMZ and even more so after removal of the CS side chains. Moreover, we found that soluble Sema 3A enhances the CS-induced repulsion in vitro. We concluded that CS acts as a repellent for cortical interneurons and that, in addition, CS restricts secreted Sema 3A within SMZ. Thus, both molecules act in concert to repel cortical interneurons from the SMZ during tangential migration toward the cerebral cortex.