A targeted, low-throughput compound screen in aDrosophilamodel of neurofibromatosis type 1 identifies simvastatin and BMS-204352 as potential therapies for autism spectrum disorder (ASD)

Autism spectrum disorder (ASD) is a common neurodevelopmental condition for which there are no pharmacological therapies that effectively target its core symptomatology. Animal models of syndromic forms of ASD, such as neurofibromatosis type 1, may be of use in screening for such treatments. Drosophila larvae lacking Nf1 expression exhibit tactile hypersensitivity following mechanical stimulation, proposed to mirror the sensory sensitivity issues comprising part of the ASD diagnostic criteria. Such behaviour is associated with synaptic dysfunction at the neuromuscular junction (NMJ). Both phenotypes may thus provide tractable outputs with which to screen for potential ASD therapies. In this study, we demonstrate that, while loss of Nf1 expression within the embryo is sufficient to impair NMJ synaptic transmission in the larva, constitutive Nf1 knockdown is required to induce tactile hypersensitivity, suggesting that a compound must be administered throughout development to rescue this behaviour. With such a feeding regime, we identify two compounds from a targeted, low-throughput screen that significantly and consistently reduce, but do not fully rescue, tactile hypersensitivity in Nf1 P1 larvae. These are the HMG-CoA reductase inhibitor simvastatin, and the BK Ca channel activator BMS-204352. At the NMJ, both compounds induce a significant reduction in the enhanced spontaneous transmission frequency of Nf1 P1 larvae, though again not to the level of vehicle-treated controls. However, both compounds fully rescue the increased quantal size of Nf1 P1 mutants, with simvastatin also fully rescuing their reduced quantal content. Thus, the further study of both compounds as potential ASD interventions is warranted. Significance Statement No therapies currently exist that consistently and effectively target the core symptoms of autism spectrum disorder (ASD), which include altered responses to sensory stimuli. Previously it was shown that Drosophila larvae lacking expression of ASD-associated Nf1 display a heightened response to a mechanical stimulus and increased neuronal excitability, likely due to excessive Ras activity. Here, out of a screen for compounds targeting such mechanisms, we identified simvastatin and BMS-204352 to reduce the likelihood of a response in Nf1 −/- larvae following mechanical stimulation. These compounds also improved synaptic transmission defects at the neuromuscular junction. Such findings support the further study of these drugs as potential ASD therapies in the clinic.