# Neural-immune mechanisms and synaptic connectivity in psychiatric illness

> **NIH NIH P50** · BOSTON CHILDREN'S HOSPITAL · 2020 · $1,999,999

## Abstract

The pathophysiological processes underlying neuropsychiatric disorders have been unknown; as a result,
these disorders have lacked innovative medical therapies with new mechanisms of action. We recently
identified the alleles underlying the human genome's largest population-level influence on risk of schizophrenia
– a series of structural alleles of the complement C4A and C4B genes, each of which appears to affect
schizophrenia risk in proportion to the amount of C4A expression it generates in the brain. We also found that
C4 shapes synaptic refinement in a mouse model of postnatal activity-dependent synapse elimination. These
findings may help explain known features of schizophrenia, including reduced numbers of synapses in key
cortical regions and an adolescent age of onset that corresponds with developmentally timed waves of
synaptic pruning in these regions.
The goal of the work we envision for a Conte Center is to develop our understanding of neural-immune
interactions and synapses while also generating novel scientific resources that can be used to evaluate current
and future hypotheses about schizophrenia-implicated genes, neural-immune interactions, and critical periods
for synaptic refinement. Our proposed work arises from close, successful collaboration of scientists with
expertise in genomics, immunology, and neuroscience. We aim to accomplish our Center's missions through
scientific projects and cores. Project 1 will seek to understand how CNS cells regulate the expression of
complement and reprogram gene expression as they traverse critical periods in the maturation of their circuits.
Project 2 will create mice that carry human C4 genes and alleles; examining how human C4 allelic diversity
and expression levels affect microglia-mediated synaptic pruning and other processes. Project 3 will reveal the
functional consequences of complement-cascade dysregulation – both over- and under-pruning – on circuit
function and behavior. A Computational and Statistical Analysis Core will contribute to research in all three
projects by facilitating analyses of genome-wide expression data and genome sequence data. An
administrative core will coordinate biweekly lab meetings and outward-facing activities, including an annual
symposium on emerging research at the interface of neuroscience, immunology and genomics.
We hope to advance the search for molecular understanding of schizophrenia while advancing the
understanding of brain development, the interacting influences of genes and environment on brain and
behavior, and possibly general principles that could be applicable to the mechanisms and pathways that go
awry in other mental illnesses.

## Key facts

- **NIH application ID:** 9923733
- **Project number:** 5P50MH112491-04
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Michael Craig Carroll
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,999,999
- **Award type:** 5
- **Project period:** 2017-05-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9923733

## Citation

> US National Institutes of Health, RePORTER application 9923733, Neural-immune mechanisms and synaptic connectivity in psychiatric illness (5P50MH112491-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9923733. Licensed CC0.

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