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; 4) ability of shRNA to Rictor delivered into the somatosensory cortex of Fmr1 KO mice via the lentivirus expression system to correct neurologic defects. These experiments will document the ability of therapeutic strategies targeting mTORC2, Rac1/PAK and cofilin signaling to rescue spine defects, impaired synaptic maturation and autism-relevant behaviors in young Fmr1 null mice.

Public Health Relevance

Fragile X syndrome is the most common heritable disorder of mental retardation and a leading form of autism. An effective treatment for the cognitive and social interaction deficits associated with Fragile X remains an unmet medical need. The proposed research will examine the ability of therapeutic strategies targeting mTORC2 and Rac1/PAK/cofilin signaling to rescue synaptic defects in young Fmr1 KO mice. These translational studies will create a foundation for generating novel therapeutic strategies to ameliorate this serious human condition.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH092877-08
Application #
9533699
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Driscoll, Jamie
Project Start
2011-01-01
Project End
2022-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine, Inc
Department
Type
DUNS #
079783367
City
Bronx
State
NY
Country
United States
Zip Code
10461
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