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

Maria V Tejadasimon

doi:10.4172/2168-975x.1000114

Abstract

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.

Highlights

Small GTP-binding proteins: Rho family Small GTP-binding proteins are involved in many different cellular processes [1], but they are mostly known to have a role in the assembly and organization of the actin cytoskeleton [2,3,4,5], which is required for cell remodeling
Using a site-specific Rac1 knockout mouse model, we reported that these Rac1 deficient mice present aberrant dendritic spine morphology in brain areas where Rac1 was genetically removed, indicating that Rac1 is directly involved in the morphogenesis of neuronal spines [33,34]
We demonstrated that NMDA and mGluR receptor activation leads to the activation of Rac1/PAK signaling, which in turn allows long-term potentiation (LTP) and long-term depression (LTD) induction respectively

Summary

Introduction

Small GTP-binding proteins: Rho family Small GTP-binding proteins are involved in many different cellular processes [1], but they are mostly known to have a role in the assembly and organization of the actin cytoskeleton [2,3,4,5], which is required for cell remodeling. Small GTP-binding proteins and neuronal morphology Very recent studies have proposed a model for Rho GTPasemediated dendritic arbor growth in which neural activity, through NMDA and AMPA receptors, activates Rac1 and decreases RhoA activation, leading to elaboration of dendritic arbors [13]. Small GTP-binding proteins and synaptic plasticity Several studies have suggested that some small GTPases involved in the remodeling of the actin cytoskeleton are activated after LTP induction in the CA1 region of the hippocampus via NMDA receptor activation [35].

Results

Conclusion