Presynaptic Homeostatic Plasticity in Health and Disease
Homeostatic plasticity mechanisms stabilize neural function in organisms ranging from insect to human. One form, presynaptic homeostatic potentiation (PHP), rapidly stabilizes postsynaptic excitation following postsynaptic receptor perturbation through presynaptic mechanisms. The postsynaptic pathway required for this rapid process and the role of this process in neurodegenerative disease have not been elucidated. This dissertation explores both questions. Chapter 1 summarizes homeostatic plasticity processes in the nervous system during health and disease. In Chapter 2, an electrophysiology-based screen of the Drosophila kinome and phosphatome forms the basis of the characterization of a postsynaptic signaling platform that includes a required function for PI3K-cII, PI3K-cIII and the small GTPase Rab11 during the rapid and sustained expression of PHP. In Chapter 3, we use a Drosophila model of motor neuron degeneration to study the induction of homeostatic plasticity during disease. In Chapter 4, the signals for induction of PHP are explored. Chapter 5 characterizes the first genetic mutation in the glutamate subunit GluRIIB. Finally, in Chapter 6, future directions for research on homeostatic plasticity and neurodegenerative disease are discussed.