# Microglial Phagocytosis of Dendritic Spines in Veterans with Schizophrenia

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2021 · —

## Abstract

Schizophrenia (SZ) is a severe and chronic psychiatric illness characterized by cognitive dysfunction. SZ
has a higher prevalence in Veterans and is associated with increased disability and mortality in Veterans.
Genome-wide association studies have identified variants of microglia-related genes as risk factors for SZ.
How such genetic factors might be manifest as molecular alterations in microglia in SZ is not clear.
Understanding microglial function in SZ is important because microglia are involved in the phagocytosis of
dendritic spines on pyramidal neurons. Spines, which receive most of the excitatory input to pyramidal
neurons, are critical mediators of the cognitive functions that are impaired in SZ. Spine density is lower
principally in deep layer 3 of the prefrontal cortex (PFC) in SZ, and PFC layer 3 has been reported to subserve
cognitive processes affected in the illness. Thus, we hypothesize that the dendritic spine deficit in deep
layer 3 of the PFC in SZ is due to increased phagocytosis of spines by microglia.
 Testing our central hypothesis requires answering the following questions. First, do microglia in SZ show a
profile of critical molecular features that enables increased spine phagocytosis (Aim 1)? We will quantify levels
of both newly discovered and established transcripts that are selectively expressed by microglia and are
involved in phagocytosis of dendritic spines (or the inhibition of phagocytosis) in laser microdissected deep
layer 3 of PFC area 46 in SZ (n=32; 50% Veterans) and unaffected comparison subjects (n=32; 50%
Veterans). We predict that SZ subjects have higher mRNA levels of microglia-specific markers that promote
spine phagocytosis and lower mRNA levels of markers that inhibit phagocytosis. We will also use a novel
quadruple-label RNAscope approach to quantify transcript levels in individual microglia to determine if all, or
only some, microglia show molecular alterations in SZ. We predict that transcripts promoting spine
phagocytosis are elevated in only a subset of microglia in SZ, which could account for findings that spine
density is ~20% lower and most prominent in deep layer 3 of the PFC in SZ.
 Second, are spine deficits in deep layer 3 of the PFC in SZ associated with molecular and morphological
features that indicate increased spine phagocytosis in nearby individual microglia (Aim 2)? Microglia and their
associated processes have their own individual territorial organization, permitting the quantification of dendritic
spines located exclusively within the territory of an individual microglia. Therefore, in the same subjects studied
in Aim 1, we will use a quintuple-label confocal immunofluorescence microscopy approach to quantify the
density of spines identified using two markers within 3D sampling regions constrained to the territorial domain
of individual microglia. We will also quantify levels of CR3, which is involved in complement-mediated
microglial phagocytosis of spines, and CD68, a phagocyt...

## Key facts

- **NIH application ID:** 10106456
- **Project number:** 5I01BX004237-02
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** DAVID W VOLK
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10106456

## Citation

> US National Institutes of Health, RePORTER application 10106456, Microglial Phagocytosis of Dendritic Spines in Veterans with Schizophrenia (5I01BX004237-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10106456. Licensed CC0.

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