Aberrant Rac1/cofilin signaling controls impaired spine structure, synaptic function, and sensory processing in Fragile X Syndrome

Abstract

Fragile X Syndrome (FXS) is the most common inherited cause of intellectual disability and autism. The primary cause of FXS is a CGG trinucleotide repeat expansion of the FMR1 gene leading to its hypermethylation and transcriptional silencing. This triggers the loss of FMRP, an RNA binding protein that controls translational repression of mRNAs critical to neuronal development, synaptic plasticity and dendritic spine architecture. The molecular mechanisms linking loss of FMRP to an overabundance of immature dendritic spines, the FXS neuroanatomical hallmark thought to underlie synaptic dysfunction and impaired cognition remains unclear. For my thesis research I show that the actin depolymerizing factor cofilin, a downstream target of the Rho GTPase Rac1, is dysregulated and causally related to spine abnormalities in the somatosensory cortex of Fragile X mice. Elevated cofilin phosphorylation and actin polymerization coincided with abnormal spines and glutamatergic synaptic transmission during a critical period of postnatal development. Viral delivery of constitutively active cofilin by stereotaxic injection into the somatosensory cortex corrected spine defects in Fragile X mice. Inhibition of the Rac1 effector PAK restored cofilin signaling, synapse function and sensory processing. These findings demonstrate causality between aberrant Rac1/cofilin signaling, altered glutamatergic synaptic transmission, and impaired sensory processing in FXS and uncover an important role for cofilin in the spine defects associated with this devastating human condition.;Another hallmark feature of FXS is elevated basal protein synthesis, which is considered a major contributor to FXS brain pathophysiology. ERK and mTOR are key signaling molecules in two prominent pathways that regulate protein synthesis. I show that the effect of loss of FMRP on these pathways is brain region specific. In contrast to the hippocampus, ERK (but not mTOR) signaling is elevated in the neocortex of Fragile X mice. Elevated ERK activity causes overactivation of p90-ribosomal S6 kinase (RSK) and hyperphosphorylation of ribosomal protein S6. Audiogenic seizures in Fragile X mice, which mimic sensory hypersensitivity in Fragile X humans, are prevented by RSK inhibition. Collectively these findings identify cofilin and RSK as therapeutic targets for FXS and suggest the therapeutic potential of drugs for FXS treatment may vary in a brain region specific manner.