Summary CXCL12/CXCR4 signaling is critical for cortical interneuron migration and their final laminar distribution. No information is yet available on CXCR7, a newly defined CXCL12 receptor. Here we demonstrated that CXCR7 regulated interneuron migration autonomously, and non-autonomously through its expression in immature projection neurons. Migrating cortical interneurons co-expressed Cxcr4 and Cxcr7, and Cxcr7−/− and Cxcr4−/− mutants had similar defects in interneuron positioning. Ectopic CXCL12 expression and pharmacological blockade of CXCR4 in Cxcr7−/− mutants showed that both receptors were essential for responding to CXCL12 during interneuron migration. Furthermore, live imaging revealed that Cxcr4−/− and Cxcr7−/− mutants had opposite defects in interneuron motility and leading process morphology. In vivo inhibition of G i/o) signaling in migrating interneurons phenocopied the interneuron lamination defects of Cxcr4−/− mutants. On the other hand, CXCL12 stimulation of CXCR7, but not CXCR4, promoted MAP-kinase signaling. Thus, we suggest that CXCR4 and CXCR7 have distinct roles and signal transduction in regulating interneuron movement and laminar positioning.
Interneurons are born in subcortical germinative zones and tangentially migrate in multiple streams above and below the developing cortex, and then, at the appropriate developmental stage, migrate radially into the cortex. The factors that control the formation of and the timing of exit from the streams remain obscure; moreover, the rationale for this complicated developmental plan is unclear. We show that a chemokine, Cxcl12, is an attractant for interneurons during the stage of stream formation and tangential migration. Furthermore, the timing of exit from the migratory streams accompanies loss of responsiveness to Cxcl12 as an attractant. Mice with mutations in Cxcr4 have disorganized migratory streams and deletion of Cxcr4 after the streams have formed precipitates premature entry into the cortical plate. In addition, constitutive deletion of Cxcr4 specifically in interneurons alters the regional distribution of interneurons within the cortex and leads to interneuron laminar positioning defects in the postnatal cortex. To examine the role of interneuron distribution on the development of cortical circuitry, we generated mice with focal defects in interneuron distribution and studied the density of postnatal inhibitory innervation in areas with too many and too few interneurons. Interestingly, alterations in IPSC frequency and amplitude in areas with excess interneurons tend toward normalization of inhibitory tone, but in areas with reduced interneuron density this system fails. Thus, the processes controlling interneuron sorting, migration, regional distribution, and laminar positioning can have significant consequences for the development of cortical circuitry and may have important implications for a range of neurodevelopmental disorders.
One striking feature of dentate gyrus development, distinct from the other cortical structures, is the relocation of neural precursors from the ventricular zone to the forming dentate pole to produce a lifelong neurogenic subgranular zone (SGZ). In this study, we demonstrate that dentate progenitors first dwell for up to 1 week in a previously unrecognized neurogenic zone intimately associated with the pial meningeal surface lining the outer edge of the forming dentate. This zone also serves as the organizational matrix for the initial formation of the dentate glial scaffolding. Timely clearance of neural precursors from their transient location depends on reelin, whereas initial formation of this transient stem cell niche requires Cxcl12-Cxcr4 signaling. The final settlement of the neural precursors at the subgranular zone relies on a pertussis toxin-sensitive pathway independent of Cxcl12-Cxcr4 signaling. Furthermore, genetic fate-mapping analysis suggests that subpial precursors contribute to the SGZ formation. These results demonstrate that the relocation of neural precursors in the dentate gyrus consists of discrete steps regulated by multiple pathways.
How the billions of synapses in the adult mammalian brain are precisely specified remains one of the fundamental questions of neuroscience. Although a genetic program is likely to encode the basic neural blueprint, much evidence suggests that experiencedriven activity through NMDA receptors wires up neuronal circuits by inducing a process similar to long-term potentiation. To test this notion directly, we eliminated NMDA receptors before and during synaptogenesis in single cells in vitro and in vivo. Although the prevailing model would predict that NMDA receptor deletion should strongly inhibit the maturation of excitatory circuits, we find that genetic ablation of NMDA receptor function profoundly increases the number of functional synapses between neurons. Conversely, reintroduction of NMDA receptors into NR1-deficient neurons reduces the number of functional inputs, a process requiring network activity and NMDA receptor function. Although NMDA receptor deletion increases the strength of unitary connections, it does not alter neuronal morphology, suggesting that basal NMDA receptor activation blocks the recruitment of AMPA receptors to silent synapses. Based on these results we suggest a new model for the maturation of excitatory synapses in which ongoing activation of NMDA receptors prevents premature synaptic maturation by ensuring that only punctuated bursts of activity lead to the induction of a functional synapse for the activity-dependent wiring of neural circuitry.AMPA receptor ͉ long-term potentiation C onsiderable evidence links NMDA receptor activation to the maturation of excitatory circuitry during brain development (1-3). Most studies, however, have relied on widespread pharmacological inhibition or broad genetic deletion of NMDA receptors to explore their involvement in synaptic development (4-8). To avoid indirect effects that such manipulations might have by generally altering network activity (9-11), we abolished NMDA receptor protein expression in sparsely distributed cells in the hippocampus by introduction of CRE recombinase to neurons in a floxed NR1 mouse (NR1 fl/fl ) (12). Mosaic deletion permitted simultaneous paired whole-cell recordings from CRE-expressing and untransfected neighboring cells to provide a rigorous, quantitative, and internally controlled comparison of the physiological effects of NR1 deletion. ResultsFirst, we biolistically transfected a plasmid encoding CRE recombinase into cells in organotypic hippocampal slice cultures from NR1 fl/fl mice. The low efficacy of this transfection technique leads to NR1 deletion in only a few cells in the slice. A GFP reporter in the construct identified CRE-expressing cells. Two weeks after transfection, synaptic NMDA currents were strongly reduced in GFP ϩ neurons but not in their untransfected neighbors (Fig. 1a, I transfected /I control ϭ 0.23 Ϯ 0.03, n ϭ 41 pairs, P Ͻ 10 Ϫ11 ). As a control, transfection of CRE on its own into wild-type slices did not significantly affect NMDA or AMPA receptor-mediated synaptic currents [NMDA: I t...
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