Identification of pharmacological treatments for behavioral defects in Drosophila models of RASopathy

RASopathies are a group of genetic disorders caused by mutations in genes that primarily affect the RAS/MAPK signaling pathway. These disorders are characterized by clinical features such as cutaneous and skeletal manifestations, short stature, a high incidence of leukemias and intellectual disability. Aiming to identify pharmacological therapies for cognitive impairments, we evaluated the impact of different mutations (cswA72S, SOSA552G, and Rasv12) on behavioral variables using Drosophila as a model, and subsequently, assessed the effect of a pharmacological treatment. Using a contextual paradigm, we analyzed two cognitive processes: context habituation (defined as the progressive decrease in response to repeated exposure to a novel environment) and recognition memory (the ability to discriminate novel stimuli from familiar ones). These processes were quantified using behavioral indices and locomotor activity tracking. Our results revealed differences in the behavioral phenotypes of cswA72S, SOSA552G, and RasV12 compared with control genotypes. Also, the dose-response curve using rosuvastatin (a pharmacological strategy to negatively modulate RAS/MAPK signaling) demonstrated concentration-dependent effects. These preliminary results allow us to conclude that the fly models of RASopathies are sensitive enough to detect behavioral phenotypes and effects in the pharmacological assays.