Aberrant Rac1-cofilin signaling mediates defects in dendritic spines, synaptic function, and sensory perception in fragile X syndrome

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Science Signaling  07 Nov 2017:
Vol. 10, Issue 504, eaan0852
DOI: 10.1126/scisignal.aan0852

Rac1-PAK signaling a target for FXS therapy?

The inherited intellectual disability and autism-associated disorder fragile X syndrome (FXS) is caused by the loss of the mRNA-binding protein FMRP and characterized by an increased formation, but impaired maturation, of dendritic spines. Spine outgrowth and maturation are dependent on actin polymerization-depolymerization dynamics. Pyronneau et al. found that loss of FMRP in mice increased the abundance and activity of the GTPase Rac1. Rac1 activated the kinases PAK and LIMK1, which inactivated cofilin, thus preventing actin depolymerization dynamics. A pharmacological inhibitor of PAK decreased the number of immature spines and improved sensory processing in FXS model mice, suggesting that targeting this pathway may be therapeutic in patients.


Fragile X syndrome (FXS) is the most common inherited cause of intellectual disabilities and a leading cause of autism. FXS is caused by a trinucleotide expansion in the gene FMR1 on the X chromosome. The neuroanatomical hallmark of FXS is an overabundance of immature dendritic spines, a factor thought to underlie synaptic dysfunction and impaired cognition. We showed that aberrantly increased activity of the Rho GTPase Rac1 inhibited the actin-depolymerizing factor cofilin, a major determinant of dendritic spine structure, and caused disease-associated spine abnormalities in the somatosensory cortex of FXS model mice. Increased cofilin phosphorylation and actin polymerization coincided with abnormal dendritic spines and impaired synaptic maturation. Viral delivery of a constitutively active cofilin mutant (cofilinS3A) into the somatosensory cortex of Fmr1-deficient mice rescued the immature dendritic spine phenotype and increased spine density. Inhibition of the Rac1 effector PAK1 with a small-molecule inhibitor rescued cofilin signaling in FXS mice, indicating a causal relationship between PAK1 and cofilin signaling. PAK1 inhibition rescued synaptic signaling (specifically the synaptic ratio of NMDA/AMPA in layer V pyramidal neurons) and improved sensory processing in FXS mice. These findings suggest a causal relationship between increased Rac1-cofilin signaling, synaptic defects, and impaired sensory processing in FXS and uncover a previously unappreciated role for impaired Rac1-cofilin signaling in the aberrant spine morphology and spine density associated with FXS.

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