# Neuroimmune interactions in Rett syndrome

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $589,041

## Abstract

Neuroimmune interactions and epigenetic mechanisms act at the interface of genetic and environmental risk
factors that determine the severity and progression of both common and rare brain disorders. A prime example
of a complex monogenic disease is Rett syndrome, an X-linked dominant neurodevelopmental disorder caused
by mutations in MECP2. Rett syndrome is epigenetic at two levels: first in the regulation of MECP2 by X
chromosome inactivation, and second because MECP2 encodes a known epigenetic regulator, methyl CpG
binding protein 2. Girls with Rett syndrome are heterozygous for MECP2 mutations that are primarily germ-line
paternal de novo events. Rett babies are born apparently normal, and then experience a regression in
cognitive and motor functions in late infancy. Mouse models of Rett syndrome also recapitulate the delay in the
onset of detectable neurological symptoms and motor deficits. While the MeCP2 protein is most highly
expressed in neurons, both human Rett patients and mouse models exhibit system-wide immune,
mitochondrial, and metabolic manifestations that are likely secondary to the causal mutation’s disruption of
neuronal homeostasis. What is lacking in the Rett field is a temporal understanding of how the molecular
signatures of disease progression in distinct cell types within the brain interact with the immune system’s
responses inside and outside of the brain. We propose to investigate the molecular signatures of critical time
points of neuroimmune pathogenesis in a novel Rett syndrome mouse model based on a human mutation.
Epigenomic investigation of specific cell types in cortex, including microglia, excitatory neurons, and inhibitory
neurons will be integrated with 1) single cell transcriptomics from hippocampus and hypothalamus, 2)
measurements of immune dysfunction, and 3) metabolite and gut microbiota profiles. The objective of the first
aim will be to characterize the time course of neuroimmune interactions in the context of symptom progression
in Rett syndrome. Results from the first aim will reveal the molecular dynamics of how immune responses
exacerbate neuronal dysfunction and vice versa. In the second aim, we propose to modulate the microglia prior
to the onset of disease progression to directly test the role of microglia in the timing and severity of symptoms
in this Rett mouse model. LPS injections in pre-symptomatic mice will be performed to activate microglia so as
to test the hypothesis that microglia activated by a “second hit” will increase the severity and speed of onset of
neurologic and motor symptoms in the Rett syndrome model. As a reciprocal experiment, microglia will be
depleted in adolescent mice using the drug PLX5622 and either allowed to replenish after short term drug
treatment or continuously depleted through adulthood to test the hypothesis that microglia are critical
mediators of symptom progression. From these experiments, we expect to obtain an integrated molecular time
course of events ex...

## Key facts

- **NIH application ID:** 9970377
- **Project number:** 5R01AA027075-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Janine M LaSalle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $589,041
- **Award type:** 5
- **Project period:** 2018-09-10 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970377

## Citation

> US National Institutes of Health, RePORTER application 9970377, Neuroimmune interactions in Rett syndrome (5R01AA027075-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9970377. Licensed CC0.

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