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