Genetic Analysis of Synaptic Function

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DESCRIPTION (provided by applicant): The efficient and stable transfer of information among neurons occurs at specialized cell-cell contact sites, called synapses but neither their structure nor their strength is static. Synapses are rearranged as neuronal circuitry is refined upon changes in neuronal activity throughout life. This process is generally believed to underlie learning and memory. Failure or even subtle changes in synaptic strength and/or wiring can disturb neuronal circuits and cause neurological, psychiatric, and/or neurodegenerative disorders. However, despite considerable progress, many molecular mechanisms that govern synaptic function are still poorly understood or not known. Using the model system Drosophila, we employed a forward genetic approach and identified a large number of gene candidates that may express critical and novel synaptic components. The major questions are now: (1) Which genes have been mutated and (2) where are the underlying proteins localized within a neuron? The proposed study is designed to answer these questions for 4 of our newly identified mutations, which all affect essential presynaptic mechanisms of synaptic transmission. The gained knowledge (molecular identity and localization of the mutated proteins and their significance for synaptic function) together with the newly produced tools (transgenes and antibodies) will then provide an essential foundation to successfully obtain large-scale federal funding to dissect the mutated molecular mechanisms underlying synaptic function. Specifically, Aim 1 will physically identify the gene locus that is mutated by the synaptic mutations B332, B689, B773, and B936. This will be achieved by genetically mapping the mutation to a small number of genes, which will then allow a molecular identification of the mutation and an association of the mutation with a particular gene. Aim 2 will resolve the tissue-specific and subcellular localization of the newly identified proteins. The proposed identification and subsequent functional analysis of new components governing synaptic structure and/or function will not only advance our basic biochemical knowledge but may also yield critical insights into the pathologies of homologous proteins in human and accelerate the development of new concepts for detecting, treating, and/or preventing neurological and psychiatric disorders.