Pharmacological Rescue of Hippocampal Fear Learning Deficits in Fragile X Syndrome

Fragile X Syndrome (FXS) is the leading cause of autism spectrum disorder and intellectual disability and results from loss of Fragile X mental retardation protein (FMRP). In neurons, FMRP controls the translation of synaptic plasticity proteins that are implicated in learning and memory. FMRP also regulates development- and experience-dependent actin cytoskeleton remodeling within dendritic spines through the small Rho GTPase Rac1. Modulation of Rac1 activity is critical during synaptic plasticity as well as learning and memory. We have previously shown that FXS mouse models exhibit learning and memory deficits as well as hyperactive Rac1 in the hippocampus. To determine whether pharmacological inhibition of Rac1 in FXS improves cognitive impairment, FXS mice were treated with the specific Rac1 inhibitor NSC23766, followed by fear conditioning. Whereas non-cognitive functions were unaffected, hippocampus-related memory improved in FXS mice treated with the Rac1 inhibitor. Furthermore, long-term potentiation in hippocampal slices from FXS mice was increased after incubation with the Rac1 inhibitor. Together, these observations indicate that modulation of Rac1 may provide a novel therapeutic target in the treatment of cognitive impairment in FXS.