# Regulation of Synaptic engulfment by human C4

> **NIH NIH P50** · BOSTON CHILDREN'S HOSPITAL · 2021 · $561,471

## Abstract

Project 2: How does human C4 allelic diversity affect microglia-mediated synaptic pruning?
Abstract:
Schizophrenia (SCZ) patients exhibit excessive loss of grey matter and decreased dendritic spine density,
suggesting that abnormal synaptic pruning may contribute to SCZ etiology. Genetic studies indicate that
complement C4A is a susceptibility factor for SCZ, although it is not clear if this link is a result of increased
complement expression in the brain or in the periphery, or both. The complement system is a major mediator of
inflammation in the periphery and over expression of C4 could induce release of pro-inflammatory cytokines that
induce pathology affecting both the periphery and the CNS. The human C4 locus encodes two highly conserved
isoforms named C4A (acidic) and C4B (basic) which differ overall by only four amino acid differences. The
differences are functionally important in binding to target sites. In the brain, C4 localizes to synapses and is
required for synaptic pruning in the developing visual system. Whether the two isoforms differ in binding
efficiency to synapses has not been reported. SCZ patients express elevated levels of C4A relative to C4B in
the CNS suggesting that the level of local expression of C4 in the brain may also be an important factor in
disease. To help address these questions, we have developed novel strains of mice that express the common
alleles of human C4, i.e. C4A only, C4B only or C4A and C4B, and crossed them to the C4-deficident
background. In addition, we have used gene editing to alter the murine C4 locus to express the human C4A-
or C4B-like isotypic region. Given the importance of complement C4 in synapse elimination in the murine visual
system, will use these mice to test our hypothesis that chemical differences in C4 combined with increased level
of local expression affect binding to synapses and directly affect the efficiency of synapse elimination by activated
microglia. Two specific aims are proposed:
Aim 1: How do the activities of C4A and C4B differ in the periphery and CNS?
This aim will precisely define how C4A and C4B functional differences affect developmental synaptic pruning and
microglia activity in the LGN.
Aim 2: What are the effects of complement overexpression on synaptic pruning?
This aim will test for the first time the idea that complement overactivation stimulates excessive synaptic pruning using
mouse models designed to model C4A expression in SCZ.

## Key facts

- **NIH application ID:** 10136094
- **Project number:** 5P50MH112491-05
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Michael Craig Carroll
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $561,471
- **Award type:** 5
- **Project period:** 2017-05-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136094

## Citation

> US National Institutes of Health, RePORTER application 10136094, Regulation of Synaptic engulfment by human C4 (5P50MH112491-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10136094. Licensed CC0.

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