There is increasing evidence that neural function is stabilized by homeostatic signaling systems in organisms ranging from Drosophila to mouse and human. In each example, homeostatic signaling systems were identified following an experimental perturbation of neuronal or muscle excitability. In each experiment, the cells responded to the experimental perturbation by modulating ion channel abundance or synaptic transmission to counteract the perturbation and re-establish normal activity levels. It is now widely hypothesized that defective homeostatic signaling will contribute to the cause or progression of neurological disease. However, clear links between homeostatic signaling and disease will require a detailed cellular and molecular understanding of the underlying signaling systems. Currently, the molecular basis of homeostatic signaling remains largely unknown. Over the past ten years, we have established a model system for the rapid identification and characterization of genes involved in homeostatic signaling in the nervous system of Drosophila melanogaster. Among our recent successes has been the demonstration that a schizophrenia associated gene in human, dysbindin, is critical for homeostatic signaling. In preliminary data we identified two novel proteins that control homeostatic signaling within the presynaptic nerve terminal including a novel protein kinase and protein phosphatase. We propose to characterize these new genes and define how they function during homeostatic signaling. Both genes are highly conserved in human.
Homeostatic signaling systems are believed stabilize neural circuitry and it is now widely believed that defective homeostatic signaling may contribute to the cause or progression of diverse neurological disorders including schizophrenia, autism-spectrum disorders, epilepsy and Alzheimer?s. We have established a rapid, cost effective system for the discovery of genes that are involved in homeostatic signaling. Gene identification and characterization are critical steps that may ultimately lead to better therapeutics for diverse neurological diseases. !
| Gaviño, Michael A; Ford, Kevin J; Archila, Santiago et al. (2015) Homeostatic synaptic depression is achieved through a regulated decrease in presynaptic calcium channel abundance. Elife 4: |
| Ford, Kevin J; Davis, Graeme W (2014) Archaerhodopsin voltage imaging: synaptic calcium and BK channels stabilize action potential repolarization at the Drosophila neuromuscular junction. J Neurosci 34:14517-25 |
| Parrish, Jay Z; Kim, Charles C; Tang, Lamont et al. (2014) Krüppel mediates the selective rebalancing of ion channel expression. Neuron 82:537-44 |
| Davis, Graeme W (2013) Homeostatic signaling and the stabilization of neural function. Neuron 80:718-28 |
