|dc.description.abstract||Autism is a complex neurodevelopmental disorder characterized by social deficits, communication and language impairments, and restricted or stereotyped patterns of behavior. Intellectual disability (ID), reported in nearly 70% of those with autism, is a pervasive co-morbidity that exacerbates cognitive functions and impedes behavioral development. The most effective treatment for autism and ID are behavior-based interventions such as Applied Behavior Analysis (ABA) that require rigorous training methodologies. Furthermore, treatment must be started early and must be continuous and consistent for optimal efficiency. The high cost of behavior therapies and demanding schedule often precludes a successful outcome.
Over the years, studies have revealed structural and functional synaptic impairments in autism and ID in areas important for cognitive functions such as learning and memory formation. The observation in these learning disabilities that repeated training can overcome cognitive deficiencies suggests that mechanisms of learning and memory are not entirely defective. Autism and ID have been found to share dysregulation of molecular signaling cascades involved in synaptogenesis, spinogenesis and synaptic plasticity. The structural integrity of synapses and dendritic spines within those synapses relies on the underlying actin cytoskeleton. Examination of post-mortem brain tissue of autistic individuals reveals not just an unusually high number of dendritic spines but a high density of immature spines. Post-mortem brain tissue also exhibits high levels of the small Rho GTPase Rac1, a well-recognized regulator of actin dynamics at the synapse. The integral role of Rac1 in dendritic spine development, synaptic plasticity, and learning and memory has been extensively studied. Together these studies present Rac1 as an intriguing target in the treatment of cognitive deficits associated with autism and ID.
Herein, we studied whether regulation of Rac1 might represent a promising treatment for cognitive impairment in autism, using Fragile X syndrome (FXS) as a model. FXS is the leading single gene cause of autism and ID. Neurons express a high density of underdeveloped dendritic spines in FXS humans and animal models. Synaptic plasticity deficits are prevalent throughout the brains of FXS mouse models including the cortex and hippocampus, areas critical for various forms of learning and memory. Moderate to severe learning deficiencies are also characteristic in FXS patients and is paralleled in mouse models. Therefore, FXS is an ideal model in the clinical and laboratory setting to investigate therapies aimed at autism and ID. In FXS mouse models, hyperactive Rac1 has been demonstrated in hippocampus and cortex where dendritic spine abnormalities are a common feature.
Our results show that in the Fmr1 KO mice (an animal model of FXS) deficits in memory and synaptic plasticity are associated with the presence and localization of Rac1. Furthermore, treatment of Fmr1 KO mice with a specific Rac1 inhibitor improves memory and increases hippocampal LTP. Taken together these observations show that Rac1 may contribute to FXS related learning and memory impairments in humans. Importantly, this study suggests that targeting Rac1 in FXS may rescue cognitive impairments. Such a therapy may be translated into broader applications in autism and ID.||