# Patient-derived Models of Synaptic Pruning in Schizophrenia

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $643,013

## Abstract

Schizophrenia is a chronic, disabling, and strongly heritable illness. Postmortem studies suggest reduced
cortical dendritic spine density among schizophrenia patients, consistent with structural neuroimaging
studies. Likewise, genomic data links schizophrenia-associated common risk variants of greatest effect to
disrupted pruning in a rodent model. These convergent lines of evidence suggest that microglia-mediated
pruning abnormalities may be responsible for the observed neuropathology in schizophrenia, extending the
recognized importance of selective engulfment of synapses by microglia as a means of pruning in normal
neurodevelopment. However, large-scale functional studies of human microglia in disease are hampered
by difficulties in obtaining living cells from individuals with schizophrenia amenable to rapid screening and
quantitative functional assessments.
 The investigators have recently developed and validated patient-specific models of microglia-mediated
pruning by reprogramming induced microglial cells from patient blood isolated monocytes, and assaying
them with isolated synapses (synaptosomes) derived from neural cultures differentiated from induced
pluripotent stem cells (iPSCs). In preliminary studies, they have demonstrated robust evidence of
abnormalities in both microglia as well as synaptosomes from individuals with schizophrenia, and rescued
such abnormalities in a dose-responsive fashion with a small molecule probe.
 The proposed investigation will confirm and extend these results using a very large patient-derived
cellular biobank developed by the investigators. Specifically, this study will generate new and fully
characterized induced microglia cultures and iPSC-derived neural cultures from 50 individuals with
schizophrenia and 50 age, sex, and ancestry-matched healthy controls. These patient-derived reagents will
be utilized in an assay to examine functional differences in microglia-mediated synaptic pruning from
patients and controls (Aim 1). These assays will also be applied to screen small molecules to identify
additional modulators of synaptic pruning, building on promising preliminary data (Aim 2). In parallel, high
throughput chemical genomic methods will be applied to characterize transcriptomic effects of these small
molecule perturbagens on microglia, providing insight into mechanism of action and facilitating further
chemical screens (Aim 3).
Together, these studies will further validate the platform for future high-throughput screening efforts aimed
at novel therapeutics. The project brings together a team with expertise in cellular modeling,
transcriptomics, clinical phenotyping, and small molecule screening. Beyond investigating these principal
hypotheses, the project will create a critical resource for the neurobiological community, with high-
dimensionality data extending a fully annotated and shareable biobank of patient and healthy control cells.

## Key facts

- **NIH application ID:** 9981011
- **Project number:** 5R01MH120227-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** ROY H. Perlis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $643,013
- **Award type:** 5
- **Project period:** 2019-07-19 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981011

## Citation

> US National Institutes of Health, RePORTER application 9981011, Patient-derived Models of Synaptic Pruning in Schizophrenia (5R01MH120227-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9981011. Licensed CC0.

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