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-edge technologies including SIM and two-photon imaging, in utero electroporations, slice electrophysiology, protemics, multi-array electrode recordings, and high-content imaging screens, to pursue the following Aims: 1) Mechanisms underlying synaptic sub-phenotypes in 16p11.2 microduplication disorder; 2) Mechanisms underlying dendritic sub-phenotypes in 16p11.2 microduplication disorder. 3) Pharmacological reversal of 16p11.2 duplication phenotypes. The proposed studies are novel and impactful, given that the 16p11.2 duplication is a major psychiatric risk factor and its synapto-dendritic impact has not yet been investigated. If successful, this proposal will be the first to demonstrate that cellular subcompartment-specific proteomics and highly penetrant monogenic disease genes within the CNV can be harnessed to identify novel mechanisms whereby a driver within the CNV can regulate a protein network outside of the CNV. Such cellular compartment-specific protein network alterations, not predicted by global mRNA profiling, could underlie specific disease sub-phenotypes. Such phenotypes could be be reversed globally by targeting network hubs, opening novel strategies for the treatment of psychiatric disorders.

Public Health Relevance

Copy number variations, including the 16p11.2 duplication, play key roles in the etiology of psychiatric disorders increasing risk up to 30 fold. However, their pathogenic mechanisms are not well understood, preventing the development of treatments. We will use an integrated approach spanning cultured neurons, mouse models, and patient-derived iNs, to characterize the mechanisms and pharmacologically reverse synaptodendritic alterations in 16p11.2 duplication disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH097216-06
Application #
9402750
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Meinecke, Douglas L
Project Start
2012-02-20
Project End
2022-04-30
Budget Start
2017-08-01
Budget End
2018-04-30
Support Year
6
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Physiology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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