# Synaptic and dendritic dysfunction in psychiatric disorders

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $588,121

## Abstract

ABSTRACT
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 alterat...

## Key facts

- **NIH application ID:** 9932483
- **Project number:** 5R01MH097216-09
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Peter Penzes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $588,121
- **Award type:** 5
- **Project period:** 2012-02-20 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932483

## Citation

> US National Institutes of Health, RePORTER application 9932483, Synaptic and dendritic dysfunction in psychiatric disorders (5R01MH097216-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9932483. Licensed CC0.

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