# DNA methylation as a mechanism for reduced dendritic spine density in schizophrenia

> **NIH NIH K23** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $187,704

## Abstract

7. Project Summary/Abstract.
Schizophrenia (SZ) is a devastating psychiatric disorder with limited treatment options. Disruptions in cortical
circuitry are a key feature of SZ pathology and pathophysiology. Reduced dendritic spine density (DSD) in
cortical layer 3 is among the most consistently observed cortical circuit abnormalities in postmortem studies of
SZ, affecting multiple brain regions including the superior temporal gyrus (STG). Reduced DSD is thought to
underlie multiple symptom domains in SZ including auditory processing deficits that impair social cognition and
auditory hallucinations, however, the mechanisms that contribute to reduced DSD are poorly understood. DNA
methylation (DNAm), the addition of a methyl group to a cytosine nucleotide, is a regulator of gene transcription.
Given that (1) DNAm is altered in the brains of SZ subjects and (2) DNAm is altered in other contexts
characterized by DSD abnormalities, DNAm is a strong candidate mechanism for reduced DSD in SZ. Despite
evidence suggesting a role for DNAm in regulation of DSD, the relationship between DNAm and reduced DSD
in SZ has not previously been explored. We propose studies to test the hypothesis that reduced DSD in SZ
results, in part, from the altered transcription of multiple genes caused by alterations in DNAm.
First, we will assess genome-wide, site-specific DNAm selectively in layer 3 of STG in a large SZ-NPC cohort
for which DSD has already been characterized. Then, we will hone in on the DNAm-DSD correlations, and the
DNAm-gene transcription relationships that may mediate those correlations, in STG layer 3 PYR neurons.
Finally, we will test the causal relationship between DNAm and DSD by using the CRISPR/Cas9 system to alter
candidate gene DNAm in a genome-region-specific manner and measure DSD in neuron cultures. To
compliment this research project, I have developed an innovative, comprehensive, and multidisciplinary training
plan to facilitate my transition to independent investigator.
Upon completion of the proposed research and training plans, I will be an expert in psychiatric epigenetics,
generally, and in applying cutting-edge approaches to the study of dendritic spine pathology in SZ, specifically.
Few researchers have the necessary background and training to connect the multiple levels of investigation—
clinical observation/behavior, circuits, neurons, transcript expression, epigenetic modifications, and genetic
code—necessary to make innovative and clinically-relevant contributions to understanding the epigenetic
mechanisms of psychiatric disorders. It is with this unique combination of background and training, that I will
establish my independent, NIH-funded lab and submit for R01 funding in year 3 of my K23 award period.

## Key facts

- **NIH application ID:** 9898462
- **Project number:** 5K23MH112798-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Brandon C McKinney
- **Activity code:** K23 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $187,704
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898462

## Citation

> US National Institutes of Health, RePORTER application 9898462, DNA methylation as a mechanism for reduced dendritic spine density in schizophrenia (5K23MH112798-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9898462. Licensed CC0.

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