BROADIE, KENDAL IBN - 9722213 Movement, behavior and higher brain function all require nerve cells to transmit information to each other, and to muscle cells. Information travels along the nerve cell in the form of an electrical impulse, and is transmitted to another cell via a special communication link called a synapse. The objective of this research is to understand the mechanisms of synapse formation and function. One powerful approach is to use genetics and molecular biology in the fruitfly Drosophila melanogaster. Genetic mutants which lack a particular component of the synapse are studied to determine the normal function of that component in synaptic mechanisms. The fly neuromuscular junction (NMJ), a synapse formed between a motor nerve cell and a muscle, is well suited for these investigations because it is large and accessible for physiology studies. Recently, a family of four integrin proteins were shown to be present at the Drosophila NMJ. Integrins are proteins which span cell membranes and are known to be important in adhesion and for relaying information across the membrane. Integrins are always found as pairs: one alpha subunit and one beta subunit make a functional protein. At the Drosophila NMJ, four of these integrin subunits have intriguing expression domains; one alpha-subunit is present in the nerve cell membrane, two alpha-subunits are present in the muscle membrane and a single beta-subunit is present on both sides of the synaptic cleft. Unlike other synaptic proteins, these integrins show a distinctive onset of expression in the NMJ, following embryonic development and concurrent with the onset of overt synaptic plasticity, the use-dependent modification of synaptic morphology and function. Moreover, a mutation in one of these integrin subunits causes a specific loss of short-term memory. These results suggest that integrins are playing important, specific roles in the mature synapse, possibly mediating a form of plasticity unde rlying higher brain functions including memory. We propose to investigate integrin function at the synapse by genetically modifying or removing each integrin subunit in turn and in combination and investigating their mutant phenotypes with a combination of functional (electrophysiology) and anatomical (light microscopy, electron microscopy) assays at the NMJ. The long-term goal is to completely characterize the function of integrins at the synapse.
