Our long term goal is to identify the molecular mechanisms that control the formation and modulation of synapses. These mechanisms control the assembly of pre- and post- synaptic components required for proper synaptic function and ensure their appropriate apposition across the synaptic cleft. Regulation of such mechanisms controls synaptic plasticity and the processes that underlie the neural basis of learning and memory, and defects in these mechanisms are likely causes of neurodevelopmental and neurodegenerative disease. The Drosophila neuromuscular junction (NMJ) is a powerful model for studying synapse formation and function. Each NMJ is composed of hundreds of presynaptic release sites, or active zones, which are directly apposed to clusters of postsynaptic receptors in the muscle membrane. Proteins that compose the presynaptic release machine cluster at each presynaptic active zone to regulate efficient vesicle release. The mechanisms that control the accumulation of release machinery proteins at active zones remain unclear, but the protein Rab3 has recently been identified as playing a novel role that controls the localization of the presynaptic release machine to synapses. In the Drosophila rab3 mutant, the majority of release sites are devoid of presynaptic proteins required for efficient vesicle release. However the mechanism by which Rab3 controls the accumulation of release machinery proteins to active zones is unknown. In an RNAi screen to identify genes that interact with Rab3 to control active zone formation, three RNAi lines were identified that enhance or suppress the rab3 mutant phenotype. The proteins disrupted by these RNAi lines along with mutants of genes known to interact with Rab3 will be studied to determine the molecular mechanisms that control active zone development and synapse formation.
This project is relevant to public health because it will enhance our understanding of how the brain develops and functions. Disruptions in the developmental processes that control how neurons connect and communicate with one another lead to neurodevelopmental diseases such as autism, mental retardation, and epilepsy. Understanding the molecules and mechanisms that control these developmental processes will aid in the development of cures for neurological disease.