# Contribution of astrocytes to the Fragile X Syndrome

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA SANTA CRUZ · 2020 · $334,059

## Abstract

Project Summary
 Fragile X Syndrome (FXS) is the most common type of mental retardation that can be linked to a single
gene mutation. FXS patients exhibit many behavioral alterations, as well as abnormal development of
synapses in the brain. Astrocytes, the major type of glia in the mammalian brain, regulate synaptic and
neuronal functions and are implicated in many developmental and degenerative neurological diseases. The
goal of this proposal is to determine the roles of astrocytes in FXS. Combining mouse genetics, live imaging,
synaptic molecular profiling, behavioral analyses and pharmacological intervention, we propose 3 aims. In Aim
1, we study how astrocytic deletion of Fragile X Mental Retardation Protein (FMRP) contributes to the synaptic
and behavioral defects observed in mice. We will generate transgenic mice in which FMRP is selectively
deleted or exclusively expressed in astrocytes. We will then compare the synaptic and behavioral phenotypes
of these mice with those of wild-type controls and FMRP full knockout mice. Aim 2 builds upon our earlier
observation that astrocyte-specific FMRP knockout mice have increased production of immature dendritic
spines of cortical neurons. We will combine in vivo imaging with mathematical modeling and synaptic
proteomic imaging to address how astrocytic deletion of FMRP affects the spatial distribution of spinogenesis
on excitatory cortical neurons, as well as synaptic/peri-synaptic neuronal and astrocytic protein expression of
newly formed spines. In Aim 3, we examine the functional changes of synapses in mice in which FMRP is
selectively deleted in astrocytes. In particular, we will examine how glial glutamate uptake and synaptic
glutamate concentration are affected in astrocyte-specific FMRP knockout mice, and determine if correcting
abnormal glutamate uptake alleviates the dendritic spine defects in these mice. The proposed work will be the
first systematic in vivo study investigating astrocytic contribution to FXS. By examining the role of astrocytes in
the neuropathology of FXS, these studies will advance our understanding of the disease and potentially point
out new therapeutic targets.

## Key facts

- **NIH application ID:** 9935160
- **Project number:** 5R01MH109475-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA SANTA CRUZ
- **Principal Investigator:** Yi Zuo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $334,059
- **Award type:** 5
- **Project period:** 2016-09-08 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9935160

## Citation

> US National Institutes of Health, RePORTER application 9935160, Contribution of astrocytes to the Fragile X Syndrome (5R01MH109475-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9935160. Licensed CC0.

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