# Astroglia-Mediated Pathogenic Mechanisms in Fragile X Syndrome (FXS)

> **NIH NIH R01** · TUFTS UNIVERSITY BOSTON · 2024 · $477,338

## Abstract

Abstract
 Fragile X syndrome (FXS) is one of the most common inherited intellectual disabilities (ID) that is caused
by transcriptional silencing of the Fmr1 gene and loss of its encoded fragile X messenger ribonucleoprotein
(FMRP). FXS manifests with cognitive impairment, hyperactivity/seizure, sensory hypersensitivity, and several
autistic features such as repetitive behaviors and social withdraw. FMRP has been shown to be primarily a RNA-
binding protein that regulates translation of many mRNAs. In the mammalian CNS, astroglial cells play active
and diverse roles in modulating synaptogenesis and synaptic functions, especially during postnatal development.
How the loss of FMRP affects astroglial development and functions, especially underlying molecular
mechanisms, just begin to be understood. MicroRNAs (miRs) are a class of noncoding RNAs with a mature
length of 20-25 nucleotides that primarily bind to the 3’UTR of target mRNAs to significantly modulate gene
expression by either inhibiting mRNA translation or inducing mRNA degradation. Biochemical and genetic
evidence in neurons have implicated important roles of miR pathways in FMRP-mediated translational regulation.
Additionally, miRs play key roles in the specification of neural progenitor cells and oligodendrocyte and microglia
developmental maturation. Surprisingly, how miRs are involved in astroglial development especially postnatal
molecular and morphological maturation is essentially unknown. This represents a significant obstacle to better
understand astroglia-mediated pathogenic pathways in FXS.
 Based on our preliminary results and progress we made during previous funding period in understanding
the role of astroglia in FXS pathogenesis, in this renewal, we propose the following aims: Aim 1: Determine the
roles of miR-128-3p in regulating postnatal astroglial development; Aim 2: Determine the pathogenic roles of
increased astroglial miR-128-3p in FXS. We have generated astroglial miR-128 conditional knock-out (Astro-
miR-128 CKO) and astroglial miR-128/Fmr1 double conditional knock-out (Astro-miR-128/Fmr1 DCKO) mice
and have generated a large amount of preliminary data to support our rationales and to demonstrate feasibility
for proposed aims. We will employ mouse genetics, primary astroglial cultures, electrophysiology, virus injections,
confocal and immunoEM imaging, and behavioral approaches to complete these aims. Outcomes from this
project will begin to define specific miRs that regulate postnatal astroglial molecular and morphological
maturation. In addition, the analysis of FXS-relevant synaptic and behavioral phenotypes on Astro-miR-128/Fmr1
DCKO mice will potentially provide a new astroglial target to modulate FXS disease development, thus will
significantly advance our understanding about astroglial mechanisms in FXS pathogenesis.

## Key facts

- **NIH application ID:** 10890712
- **Project number:** 5R01MH106490-07
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Yongjie Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $477,338
- **Award type:** 5
- **Project period:** 2016-05-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10890712

## Citation

> US National Institutes of Health, RePORTER application 10890712, Astroglia-Mediated Pathogenic Mechanisms in Fragile X Syndrome (FXS) (5R01MH106490-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10890712. Licensed CC0.

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