Small GTP-binding Proteins: A Future for the Treatment of Cognitive Disorders?

Recent findings indicate that early brain overgrowth could be a key factor in the patho-biology of autism and other disorder with learning disabilites, and that anomalous neuronal wiring might play a role when is affecting brain regions involved in cognition. Thus, precise synaptic connectivity is crucial for normal brain function and a common anatomical pathology associated with autism and cognitive disability is an alteration of that connectivity due to an irregular morphology of the dendritic spines in the neurons. For example, human patients as well as animal models of Fragile X syndrome (FXS), Neurofibromatosis, Tuberous sclerosis, and Rett syndrome, have shown a higher number of immature dendritic spines in certain regions of the brain, phenomena that has been linked with impaired learning and memory functions. However, how this deficiency is produced is not yet well understood. Evidence from our laboratory and others is pointing to a role of small GTP-binding proteins of the Rho family, which mediate actin cytoskeleton reorganization, neuronal morphogenesis and gene expression. We have reported that these proteins are critical for dendritic morphology and plasticity. They act not only in the developing brain but also in the mature nervous system. One of its members, Rac1 is highly expressed in the adult mouse hippocampus, a brain area that exhibits robust synaptic plasticity and is crucial for the acquisition of memories. Moreover, using pharmacological and genetic approaches we and others have demonstrated that Rac1 is necessary for normal long-term plasticity, spine development and learning. Interestingly, glutamate transmission, long-term plasticity and learning behavior are characteristically altered in autistic disorders that present aberrant neuronal development. Therefore, there might be a functional link between small GTP-binding proteins and certain characteristic phenotypes described in cognitive disorders and possibly autism that render interest on the small GTP-binding proteins as possible therapeutic targets for these disorders.