Justin B. Slawson, Ph.D. - US grants

DESCRIPTION (provided by applicant): In Drosophila melanogaster, experience-dependent plasticity is associated with the ability of CaMKII to become activated following a transient influx of calcium resulting from synaptic activity. The CaMKII-binding MAGUK scaffolding protein dCASK has been shown to regulate this transition, and thus contribute to CaMKII-related plasticity. Previous work has also suggested this scaffolding protein may play a role in basal motor behavior, but this role has been poorly characterized. Using new dCASK null fly mutants I have generated, I am proposing to 1) define the role of dCASK in basic locomotor function, 2) determine the molecular basis of basal and dynamic localization of dCASK to the synapse, and 3) elucidate the relationship between dCASK localization and locomotor function, I will employ high-resolution video tracking analysis to define the locomotor defects of dCASK mutants. Temporally and spatially restricted expression of dCASK will be used to map these behavioral circuits. Synaptic localization will be investigated by expressing dCASK and mutants of dCASK lacking specific domains in the null background to determine which structural features of the protein are required for synaptic localization at the larval NMJ and in adult neurons that are part of the behavioral circuit I have defined. I will also investigate the molecular basis of dCASK's role in behavior by using my domain mutants to rescue the null locomotor phenotype. These experiments will provide a solid understanding of how this scaffolding protein functions in basal locomotor behavior, and will allow us to begin to put together molecular pathways which involve this protein, including those implicated in synaptic plasticity. Understanding the role of dCASK in basal locomotor function, both at the molecular and behavioral levels, could greatly contribute to the field of movement disorders, including Parkinson's and Huntington's Disease. Furthermore, since synaptic plasticity is necessary for proper brain development as well as learning and memory, understanding the regulatory mechanisms behind these processes will prove critical for treating a wide array of disorders. Disruptions in synaptic plasticity mechanisms have been associated with neurological disorders such as Alzheimer's Disease, Schizophrenia, Down's Syndrome, addiction, and Epilepsy, as well as many types of learning disabilities. The proposed studies will not only help elucidate the mechanisms contributing to a vast array of neurological conditions, but it will also provide insight into the underpinnings of complex behavior.