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Eriny Hanna

Summer Research Description: Fragile X syndrome (FXS) is the most prevalent hereditary cause of intellectual disability (ID) and autism spectrum disorders (ASD). FXS is caused by silencing of the fragile X mental retardation 1 (FMR1) gene, which encodes a multifunctional protein with both RNA-binding and channel-binding activities that are critical for activity-dependent synaptic development and plasticity. The Drosophila FXS disease model was established 15 years ago by the Broadie Lab, and utilizes Drosophila fmr1 (dfmr1) null mutants that exhibit neural circuitry and behavioral phenotypes closely resembling the spectrum of human FXS symptoms. This study aims to use classical olfactory aversive conditioning in dfmr1 mutants to assess the efficacy of a wide range of pharmacological agents in alleviating learning acquisition and long-term memory (LTM) deficits. Manual behavioral testing proved to be vastly inefficient for a high-throughput drug screen. We therefore collaborated in the design of a fully automated training and testing system, the Linear Automated Training and Testing System (LATTS), which will be multiply arrayed to create a behavioral testing center. Arduino IDE software manages the delivery of odorants and electrical shock training, as well as the transport of animals from training to testing sites within the closed system. The 3D-printed apparatus mimics the design of the traditional manual apparatus, with a linear actuator moving an elevator centerpiece to transport animals between training and testing sites. Current drug screening results show restoration of dfmr1 null mutant learning and LTM formation with the matrix metalloproteinase inhibitor (MMPI) minocycline. In addition, the GABA-reuptake blocker nipecotic acid (NipA) effectively restores LTM, but does not improve learning, suggesting differential “drugable” pathways for learning and memory therapeutic intervention. Future experimentation will assess a wide range of additional candidate drugs, as well as test combinatorial drug effects, in this powerful FXS disease model.