# Dysregulation of mTORC2 and cofilin signaling in Fragile X Syndrome

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2021 · $417,500

## Abstract

Fragile X syndrome is the most common heritable form of intellectual disabilities and a leading genetic cause of
autism. An effective treatment for the cognitive and social interaction deficits associated with FXS is an unmet need.
The mammalian target of rapamycin (mTOR) pathway is a central regulator of cell metabolism, growth, proliferation,
survival, cap-dependent translation and the actin cytoskeleton. Whereas dysregulation of mTOR Complex 1
(mTORC1) in Fragile X is well established, a role for mTORC2 is, as yet, unclear. mTORC2 is a central regulator of
actin polymerization and spine structure and acts on the actin-depolymerizing factor cofilin implicated in synaptic
plasticity and memory. Our finding that cofilin and its upstream regulator Rac1, a small Rho GTPase and direct
target of mTORC2 implicated in actin remodeling and spine structure, are impaired in a mouse model of Fragile X
provides a functional link between FMRP, mTOR, and cofilin signaling and underscore the clinical relevance of this
work. The overall goals of the proposed research are to examine whether overactivated mTORC2 signaling is
causally linked to cofilin signaling, spine structure, and synaptic maturation in Fmr1 KO mice, and establish
mTORC2 as a novel therapeutic target for the amelioration of FXS. The underlying hypothesis is that loss of FMRP
leads to overactivated mTORC2 and cofilin signaling, which induce spine abnormalities, impaired synaptic
maturation, sensory processing and autism-relevant behaviors. We seek to test this hypothesis in the following
Aims: 1. Examine a causal relation between dysregulation of cofilin signaling and the synaptic phenotype in the
somatosensory cortex of young Fragile X mice. Experiments will examine 1) ability of a constitutively active cofilin
mutant (S3A) delivered directly into the somatosensory cortex of Fmr1 KO mice via the lentivirus expression system
to rescue spine defects; 2) ability of cofilinS3A to rescue delayed synaptic maturation of layer V neurons in the
somatosensory cortex of Fmr1 KO mice during the critical period; 3) ability of cofilinS3A to rescue impaired spike-
timing LTP at excitatory synapses in the somatosensory cortex of Fmr1 KO mice: 4) ability of a phospho-cofilin
peptide, which inhibits endogenous cofilin, to phenocopy aberrant actin polymerization, spine defects and impaired
synaptic maturation in somatosensory cortex of WT mice. 2. Identify signaling pathways upstream of aberrant cofilin
signaling and ability of pharmacologic and genetic manipulation of mTORC2 signaling to rescue the FXS phenotype.
Experiments will establish 1) mTORC2 as an upstream effector critical to aberrant cofilin signaling; 2) Rac1/PAK
signaling as a potential pathway upstream of cofilin and downstream of mTORC2 and ability of PAK inhibition to
rescue impaired spine structure, synaptic maturation and spike timing LTP; 3) deficits in sensory perception in FXS
mice and ability of PAK inhibition to rescue impaired perception; ...

## Key facts

- **NIH application ID:** 10143299
- **Project number:** 5R01MH092877-12
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** R. Suzanne Zukin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $417,500
- **Award type:** 5
- **Project period:** 2011-01-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10143299

## Citation

> US National Institutes of Health, RePORTER application 10143299, Dysregulation of mTORC2 and cofilin signaling in Fragile X Syndrome (5R01MH092877-12). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10143299. Licensed CC0.

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