We will determine whether genetic vulnerability for schizophrenia established by heterozygous deletion atchromosome 22q11 (the genomic cause of DiGeorge/Velocardiofacial/22q11 Deletion Syndrome:22q11DS)compromises genesis, migration and differentiation of GABAergic cortical interneurons. The overall goal ofour Conte Center is to evaluate the hypothesis that genetic vulnerability for schizophrenia can compromiseessential aspects of prenatal and postnatal development. 22q11 deletion is a well-established genetic risk forschizophrenia that can be modeled precisely at the genomic level in mice. In the first funding period of ourConte Center, we found that several 22q11 orthologues are expressed either in forebrain precursor cells orearly differentiating neurons in the cerebral cortex. Moreover, expression levels of these genes, includingseveral been linked independently to schizophrenia are diminished without apparent dosage compensationin a mouse model of 22q11DS. we have identified a subset of five of these genes that are expressed inforebrain progenitor cells or their postmitotic progeny. In parallel, we have found that there are consistentand significant differences in cell cycle times of forebrain precursors in the 22q11 DS mouse model. Inaddition to assessin altered proliferative characteristics, we used a novel in vitro assay for GABAergicinterneuron migration, developed as part of our efforts in the first funding period of our Conte Center, toidentify apparent migratory deficits in GABAergic neuroblasts migrating from the basal forebrain to thecortex. Finally, initial cellular analysis of the adolescent cortex in 22q11-deleted mice indicates differences inGABAergic interneuron frequency and placement. Accordingly, we propose to test the hypothesis thatgenetic vulnerability established by 22q11 deletion initiates pathogenesis in the Pan/albumin andSomatostatin positive population of GABAergic cortical interneurons by compromising the proliferation oftheir precursors, their migratory capacity as neuroblasts, and their final numbers, positions, and elaborationof connections in the early postnatal cerebral cortex. In 3 Specific Aims, we will determine whether cell cyclekinetics, self renewal, and differentiation capacity of GABAergic basal forebrain precursors is altered bydiminished expression of 22q11 genes, whether GABAergic neuroblasts migrate improperly, and whetherPan/albumin and somatostatin-expressing subsets are compromised specifically during their subsequentmaturation in the adolescent cortex. Our preliminary evidence indicates that 22q11 genes may act at eachstage of GABAergic interneuron development, and that heterozygous deletion does compromised thisprocess. Thus, we will contribute to the goals of the UNC Conte Center by determining whether specificgenetic vulnerability disrupts a critical process in cortical development, and thereby contributes tosubsequent schizophrenia pathogenesis.
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