# Functional Consequences of Aberrant Pruning on Circuits and Behavior

> **NIH NIH P50** · BOSTON CHILDREN'S HOSPITAL · 2021 · $703,030

## Abstract

Brain imaging in schizophrenia patients reveals excessive loss of gray matter, already visible in young adults at
the first psychotic episode. Post mortem brains from schizophrenia (SCZ) patients have decreased numbers of
synapses in the prefrontal cortex (PFC), a region involved in executive function and working memory. However,
it is not known whether synapse loss results from excessive developmental pruning or why schizophrenia often
becomes clinically apparent during adolescence. Dendritic spine density on layer 3 pyramidal neurons is
dramatically reduced in SCZ patients, suggesting a synapse and circuit- specific mechanism of vulnerability. As
the PFC integrates information from multiple brain regions, defects in pruning could significantly impact synaptic
connectivity, cognitive function, and behavior.
Our goal is to map the development and refinement of PFC synapses (Aim 1) and to interrogate the
functional and behavioral consequences of local and global defects in synaptic pruning (Aims 2–3). We
have identified C4A and the classical complement cascade as key mediators of synaptic pruning in the mouse
postnatal visual system (Sekar et al., 2016)(Project 2); however, it is unknown if it is also necessary in the cortex
and circuits relevant to SCZ and if aberrant pruning affects anatomical and functional connectivity and the
behaviors dependent on it. In Aim 2, we will test the hypothesis that over-activation of the complement cascade
enhances pruning in the PFC, perturbing anatomical and functional connectivity as well as behavior. We will use
global complement KO mice (C1q, C4KO) and novel hC4A-overexpressing mice (Project 2) to ask if early
postnatal pruning defects impact cortical connectivity and function later in life. We will also use viral strategies to
test if circuit-specific and temporally restricted activation and inhibition of the complement cascade is sufficient
for circuit-specific phenotypes. In Aim 3, we will seek to understand how second hits (genetic or environmental)
on a background of genetic risk (increased copy number of C4A) combine to impact neural circuit development
and behavior. We hypothesize that a second genetic hit (e.g., loss of CSMD1) or environmental hit (immune
challenge) might worsen synaptic and behavioral phenotypes in mice over-expressing the human C4A risk allele.
To link the central and peripheral effects of C4 expression explored in Projects 1 and 2, we will investigate the
potential role of the choroid plexus, a major source of cerebral spinal fluid (CSF), in the regulation of complement
and cytokine levels in the brain in Aim 3. This will lead to a better understanding of the cellular and molecular
players linking peripheral immune dysregulation to brain dysfunction and may identify novel biomarkers.

## Key facts

- **NIH application ID:** 10136095
- **Project number:** 5P50MH112491-05
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Beth Ann Stevens
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $703,030
- **Award type:** 5
- **Project period:** 2017-05-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136095

## Citation

> US National Institutes of Health, RePORTER application 10136095, Functional Consequences of Aberrant Pruning on Circuits and Behavior (5P50MH112491-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10136095. Licensed CC0.

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