# Synaptic Protein Networks, Genetic Risk, and Spine Loss in Schizophrenia

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $487,667

## Abstract

Abstract
 Schizophrenia (Sz) is a lifelong and devastating psychiatric illness with limited treatment options and no cure.
Layer 3 pyramidal cell dendritic spine loss has been repeatedly observed in multiple brain areas in schizophrenia
(Sz), including the primary auditory cortex (AI). Spine loss is postulated to underlie primary auditory cortex
processing deficits observed in Sz, contributing to impaired social cognition and auditory hallucinations in Sz.
We have shown that only smaller spines are lost in Sz Al layer 3. Recent two-photon in vivo imaging studies
have shown that new spines are small, essential for synaptogenesis, and required for new learning in adult
animals. Dendritic spine formation, stabilization, and plasticity are regulated by synaptic protein network (SynPN)
features, such as protein expression, trafficking, and phosphorylation (Phos), and a significant number of Sz risk
loci code for synaptic proteins.
 Targeted and shotgun mass spectrometry (MS) approaches found robust changes in synaptosome and Phos
levels of canonical postsynaptic proteins in Sz. These changes were not explained by corresponding changes
in homogenate levels of these proteins, suggesting that the brunt of SynPN pathology in Sz is regulated by
processes beyond protein expression (e.g. protein trafficking and activity). Nine Phos sites on eight proteins
were highly correlated with both synaptosome protein levels and small spine density. All but one of these 8
proteins have well documented roles in vesicular trafficking of postsynaptic glutamate receptors and spine
regulation. Postsynaptic glutamate signaling is one of the most significantly implicated pathways in genetic
studies of Sz. Thus, we hypothesize that: Aberrant trafficking and Phos of postsynaptic proteins is linked
to Sz genetic risk and drives small spine loss in Sz Al.
 We will test this hypothesis in an unprecedented set of parallel genomic, proteomic, and microscopy
experiments in 100 Sz and 100 matched control subjects with cutting edge computational analyses to identify
protein and Phos linked to Sz genetics and generate causal models of disease (Aim 1). We will then utilize
innovative molecular and two-photon microscopy approaches to test the effects of candidate Phos, from our
preliminary studies and high priority Aim 1 findings, on spine density, size, formation, and stability in the Al of
adult mice (Aim 2).
 These studies will identify proximal molecular events, potentially associated with Sz risk genetics, that impair
small spines in Sz Al, as well as the stage of spine formation/stabilization that is impaired. Such events can be
further investigated in vivo via CRISPR/Cas9 in future studies and have the potential to serve as targets for the
development of novel therapeutics.

## Key facts

- **NIH application ID:** 10405455
- **Project number:** 5R01MH118497-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Matthew L MacDonald
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $487,667
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10405455

## Citation

> US National Institutes of Health, RePORTER application 10405455, Synaptic Protein Networks, Genetic Risk, and Spine Loss in Schizophrenia (5R01MH118497-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10405455. Licensed CC0.

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