Synaptic and dendritic dysfunction in psychiatric disorders

Recent data emerging from large-scale genomic studies has revealed that copy number variations (CNVs) are a major class of mutations that play a key role in the etiology of psychiatric disorders, including autism (ASD) and schizophrenia (SZ), increasing risk up to 30 fold. However, the large number of genes in CNVs, and the wide variety of clinical phenotypes associated with them, has made understanding CNV-associated disorders and their genotype-phenotype correlations especially challenging. Duplications of 16p11.2 chromosomal region, occur in ASD, SZ, intellectual disability (ID), Rolandic epilepsy, and other disorders, and are among the top 2 most highly penetrant and frequent CNVs in SZ. Despite this progress in genomics, synaptic phenotypes in models of 16p11.2 CNV have not yet been thoroughly studied. The identification of robust synaptic phenotypes would result in experimentally approachable targets for treating common aspects of neuropsychiatric disorders such as cognitive dysfunction. Alterations in glutamatergic synapses and dendritic architecture have been implicated by genomic, neuropathological, and functional studies as key sites of pathogenesis in neurodevelopmental psychiatric disorders including SZ, ASD, and ID. However, the synaptic biology that contributes to the pathogenesis of CNV disorders remains largely elusive. In this renewal application we propose to investigate the impact of CNVs on synaptic and dendritic dysfunction in SZ, ASD and other neurodevelopmental disorders by focusing on the 16p11.2 duplication. We hypothesize that individual genes within the 16p11.2 locus drive distinct sub-phenotypes, often expressed as cellular compartment-specific alterations, by modulating localization of proteins encoded by genes outside the CNV. These phenotypes can be reversed by targeting network hubs. In this application, we will use an integrated approach spanning cultured neurons, mouse models, and patient-derived iNs, and a combination of cutting-ed