Association of Rac1 dysregulation and learning disability

Abnormal neuroplasticity is a hallmark of several psychiatric disorders associated with learning disabilities such as Fragile X syndrome (FXS). FXS is caused by the absence of the Fragile X Mental Retardation Protein (FMRP), which regulates mRNA translation and transport to dendritic spines. In FXS, neurons generate an unusually high density of long, thin, immature dendritic spines accompanied by aberrant long-term plasticity. Interestingly, our lab has recently demonstrated that, in the brain of an FXS mouse model, there is a correlation between lack of FMRP and over-activation of Rac1, a protein of the Rho GTPase subfamily implicated in neuronal and dendritic spine development. This mouse model also exhibits dysfunctional synaptic plasticity and deficits in cognition. Thus, we hypothesize that some of the abnormal phenotypes of the FXS model might be related to the observed Rac1 hyper-activation. This study was undertaken to determine whether Rac1 critically participates in synaptic plasticity, and to further examine a possible involvement of Rac1 in FXS. Electrophysiology experiments using hippocampal slices derived from wild-type mice revealed that pharmacological inhibition of Rac1 indeed significantly disrupts several forms of synaptic plasticity including long term depression (LTD). Moreover, by applying a Rac1 inhibitor to hippocampal slices derived from FXS mice, the exaggerated LTD characteristic of FXS was restored to wild-type levels. This suggests that increased Rac1 activity may contribute to FXS etiology. Therefore, regulation of Rac1 could provide a functional link among deficient neuronal morphology, perturbed synaptic plasticity and cognition impairment in this and other disorders.