Spine Abnormalities and Altered Plasticity Associated to Cognitive impairment involve Rac1 Signaling

Abnormal dendritic spine morphogenesis and altered synaptic plasticity have been associated with several psychiatric disorders. Fragile-X syndrome, one of such disorders, is caused by the absence of Fragile-X mental retardation protein (FMRP), an RNA-binding protein implicated in the regulation of mRNA translation and transport, leading to protein synthesis. We suggest that FMRP acts as a negative regulator on the synthesis of Rac1, a protein of the Rho GTPase subfamily that has been implicated in spine development and long-term plasticity. This study was undertaken to first verify the importance of Rac1 in dendritic spine development and synaptic plasticity, and to further examine a possible link for Rac1 in Fragile-X syndrome. Using the Cre/LoxP system and a Rac1 floxed mouse we created a tissue specific Rac1 deficient animal in which Rac1 was knocked-down in the hippocampus. Loss of Rac1 in these mice caused aberrant dendritic morphology and significantly impaired long-term potentiation and long-term depression. We further showed that, in Fmr1 knockout mice, as an animal model of Fragile-X syndrome, lack of FMRP induces an overactivation of Rac1 in the mouse brain and other organs that have been shown to be altered in this disease. Interestingly, by applying a Rac1 inhibitor to hippocampal slices from Fmr1 knockout mice during electrophysiology experiments, we were able to rescue the altered long-term depression characteristic of this animal model of Fragile-X syndrome. Thus, regulation of Rac1 may provide a functional link among deficient neuronal morphology, aberrant synaptic plasticity and cognition impairment.