January Newsletter: The GEF Trio and Its Role in Autism Spectrum Disorders

Intellectual disabilities (e.g., neurodevelopmental disorders, autism spectrum disorders [ASDs]) are associated with abnormal development of dendrites and dendritic spines. ASDs are a complex set of behaviorally defined disorders, characterized by impairments in social interaction, communication, and restricted or stereotyped behaviors. Recent studies estimate that 1% of the world-wide population has an ASD¹. Dendritic spines are comprised of F-actin and the structural and functional plasticity of spines depend upon the dynamic regulation of actin by Rho-family GTPases. Indeed, Rac and PAK effector proteins are essential regulators of normal brain development and function, including dendritic spine initiation, elongation, and branching^2-4. Recent genetic studies revealed that individuals with intellectual disabilities express mutated versions of genes involved in Rho-family GTPase signaling such as a Rho-family GTPase activating protein (GAP), the serine/threonine kinase PAK3, and the Rac/Cdc42 guanine exchange factor (GEF) aPIX5. In addition, the PAK inhibitor FRAX486 is an effective treatment for fragile X syndrome (FXS), the most common inherited form of autism and cognitive disability. FRAX486 reversed dendritic spine and behavioral abnormalities in an in vivo model of FXS⁶. Moreover, Rac1 activation or inhibition of cofilin, an actin depolymerizing protein, rescues ASD-like phenotypes in Shank3 knock-out mice, an in vivo model of ASDs^7-12.