Rescuing aberrant phenotypes and cognitive deficits in FMRP‐deficient female mice (845.6)

Abstract

Identifying the causes and pathogenic mechanisms of neurodevelopmental diseases such as Fragile X syndrome (FXS) is complex. It has been reported that, in FXS, there is an unusually high density of long, thin, immature dendritic spines accompanied by aberrant long‐term plasticity and cognitive abnormalities. Our lab has recently demonstrated that, in the brain of FXS mice, there is an over‐activation of Rac1, a protein of the Rho GTPase subfamily implicated in neuronal and dendritic spine development. This mouse model also exhibits alteration of synaptic plasticity and deficits in learning and memory. Since this particular disease is linked to the X chromosome, most of the existing studies, including ours, make use of male knockouts. Thus, this study was undertaken to provide analogous studies in FXS female mice. Expression of Rac1 levels was determined in Fmr1‐KO female mice. Furthermore, Fmr1‐KO female mice were treated with a Rac1 inhibitor and subjected to behavioral, biochemical and morphological studies to determine whether modification of the levels of Rac1 could rescue these deficiencies. We observed that pharmacological inhibition of Rac1 indeed ameliorates cognitive deficits observed in untreated Fmr1‐KO females, as measured in a fear conditioning paradigm and other associative learning and memory function tests. Our biochemical data suggested decreased levels of activated Rac1 in FXS mice and WT mice after treating with inhibitor which correlated with morphological studies showing normalization of aberrant dendritic spines which are characteristic in FXS mice. Additionally, treatment with the inhibitor protected against audiogenic seizures, a strong phenotype in this animal model of FXS. This suggests that Rac1 activity may contribute to FXS etiology, and that Rac1 could be involved in the mechanism responsible for the deficient neuronal morphology, perturbed synaptic plasticity and cognition impairment associated with this disorder.Grant Funding Source: Jérôme LeJeune Foundation (France), FRAXA Research Foundation (USA) and UH GEAR