Modulation of actin dynamics by Rac1 to target cognitive function.

The small GTPase Rac1 is well known for regulating actin cytoskeleton reorganization in cells. Formation of extensions at the surface of the cell is required for migration and even for cell invasion and metastases. Because an elevated level and hyperactivation of this protein has been associated with metastasis in cancer, direct regulators of Rac1 are currently envisioned as a potential strategy to treat certain cancers. Less research, however, has been done regarding the role of this small GTP-binding protein in brain development, where it has an important role in dendritic spine morphogenesis through the regulation of actin. Alteration of dendritic development and spinogenesis has been often associated with mental disorders. Rac1 is associated with and required for learning and the formation of memories in the brain. Rac1 appears to be dysregulated in certain neurodevelopmental disorders that present all these three alterations: mental retardation, atypical synaptic plasticity and aberrant spine morphology. Thus, to develop novel therapies for rescuing cognitive impairment, a reasonable approach might be to target this protein, Rac1, which plays a pivotal role in directing signals that regulate actin dynamics, which in turn might have an effect in spine cytoarchitecture and synaptic function. It is possible that novel drugs that regulate Rac1 activation and function could modulate actin cytoskeleton and spine dynamics, representing potential candidates to repair intellectual disability in disorders associated with spine abnormalities. Herein, we present a list of the current Rac1 inhibitors that might fulfill this role together with a summary of the latest findings concerning their function as they relate to neuronal studies. While the small GTPase Rac1 is well known for regulating actin cytoskeleton reorganization in different type of cells, it appears to be also required for learning and the formation of memories in the brain. Abnormal regulation of this protein has been associated with cognitive disabilities, atypical synaptic plasticity and abnormal morphology of dendritic spines in certain neurodevelopmental disorders. Thus, modulation of Rac1 activity using novel inhibitors might be a strategy to reestablish cognitive function.