# Pathophysiology and treatment of fragile X and related disorders

> **NIH NIH R21** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2022 · $232,649

## Abstract

Currently there are no mechanism-based therapies available for autism spectrum disorders
(ASDs) and intellectual disability (ID). Two major barriers are the identification of defective
cellular processes within the brain that disrupt behavior and cognition, and the validation of an
objective biomarker based on pathophysiology that can be used for patient stratification and
assessing treatment response. The objectives of this project are to address these deficiencies
using the mouse model of fragile X syndrome, a leading cause of human ID and ASD. Fragile X
is caused by silencing of the FMR1 gene on the X chromosome and loss of the encoded protein
FMRP. Major consequences of the loss of FMRP include disrupted regulation of protein
synthesis in neurons, altered ion channel function, and altered development of inhibitory circuits
in the cerebral cortex. Previous studies in the Fmr1 KO mouse showed that manipulations that
acutely correct alterations in basal protein synthesis also improve a wide variety of structural,
biochemical, and behavioral deficits. Thus, one promising line of research entails understanding
how the manipulations of protein synthesis restore normal neuronal function. Our studies in the
visual cortex (V1) of Fmr1 KO mice have shown that hyperexcitability of layer (L) 5 V1 neurons
is a cell-autonomous phenotype that is corrected by suppressing aberrant protein synthesis.
This phenotype may be relevant to sensory hyperresponsivity that is highly disruptive in human
fragile X and other forms of ASD, but regardless it is a useful reporter of a functional
consequence of altered protein synthesis. Remarkably, reversal of this phenotype occurs
rapidly, within 60 minutes of suppressing protein synthesis. These data implicate pathogenic
proteins with a short half-life that are rapidly depleted by inhibiting mRNA translation. In Aim 1 of
this exploratory project, we will take advantage of genetic access to a subpopulation of L5
neurons to identify these proteins. If successful, this approach will yield a list of novel
therapeutic targets specifically linked to aberrant protein synthesis in fragile X. In Aim 2, we will
assess the generality of our findings in L5, and investigate the impact of this specific pathogenic
mechanism on the function of V1 in awake mice. These experiments will yield novel functional
measures of treatment efficacy in vivo that, if translated to humans, could be used as potential
biomarkers of a specific class of pathophysiological mechanisms in fragile X and related
disorders.

## Key facts

- **NIH application ID:** 10452012
- **Project number:** 1R21NS123499-01A1
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Mark F Bear
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $232,649
- **Award type:** 1
- **Project period:** 2022-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10452012

## Citation

> US National Institutes of Health, RePORTER application 10452012, Pathophysiology and treatment of fragile X and related disorders (1R21NS123499-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10452012. Licensed CC0.

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