# Synaptic Pruning and Complement Gene in Schizophrenia: Imaging & Cellular Studies

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $576,706

## Abstract

Abstract: Multiple lines of evidence suggest that increased synaptic pruning is pathophysiologically significant
for schizophrenia (SZ). Emerging evidence suggests that genetic factors are associated with increased synaptic
pruning in SZ. Recent genome-wide association studies convincingly demonstrated that Complement (C4) gene
repeats were significantly associated with SZ risk, specifically C4A long form (C4AL). C4 protein expression in
the brains of schizophrenia patients was increased proportionate to the number of C4AL repeats. A mouse
analog of C4 was associated with increased synaptic pruning in a rodent model. We propose to develop two
independent lines of evidence on the association of genetic factors with synaptic pruning. Our in vivo approach
will longitudinally examine measures of synaptic pruning obtained using ultra-high field structural MRI and
phosphorus magnetic resonance spectroscopy (31P MRS) at 7 Tesla at baseline, 6-months and 1-year among
adolescents with early onset SZ (EOS) and healthy controls (HC), and its association with cognitive performance
(Aim 1), C4 repeats and global genetic liability measured through polygenic risk score (PGRS) (Aim 2). The
rationale for longitudinal examination of adolescent EOS and HC is supported by more prominent synaptic
pruning during adolescence. Ultra-high field structural MRI and 31P MRS at 7 Tesla provides superior resolution
and greater sensitivity for metabolite quantification. 31P MRS measures metabolites of membrane phospholipids
(MPL) across the entire brain. Decreased MPL precursors index decreased neuropil formation whereas
increased MPL breakdown products reflect neuropil contraction. Since synapses are embedded in the neuropil
and major part of membrane expansion is contributed by synapses, dendritic branches and dendritic spines,
MPL metabolite levels are proposed to provide more specific and sensitive measure of neuropil compared to
gray matter metrics. An additional measure to index neuropil contraction is through cortical thickness
measurements. PGRS is a more accurate measure of overall genetic risk conferred by genomewide variations.
Our in vitro approach will examine dendritic spine density and morphology in relation to expression of C4 proteins
- both naturalistically and with induction of over- and under- expression of C4 proteins in differentiating human
induced pluripotent stem cell (hiPSC)-derived neuronal organoids (Aim 3). Organoids are 3-dimensional
neuronal cultures that show more refined microanatomic feature capable of recapitulating some specific
functions of the brain compared to 2-dimensional cultures. In addition to providing independent evidence of
synaptic density related to C4 protein expression, hiPSC model provides some corroborative evidence for the
31P MRS and cortical thickness findings that may represent synaptic pruning. Proposing only one line of evidence
leaves open questions about the association of genetic factors with neuropil pruning. Exami...

## Key facts

- **NIH application ID:** 9967101
- **Project number:** 5R01MH115026-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Konasale M Prasad
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $576,706
- **Award type:** 5
- **Project period:** 2018-07-12 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9967101

## Citation

> US National Institutes of Health, RePORTER application 9967101, Synaptic Pruning and Complement Gene in Schizophrenia: Imaging & Cellular Studies (5R01MH115026-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9967101. Licensed CC0.

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