Characterization of behavioral mutants in Drosophila has identified a plethora of synaptic proteins and ion channels. Furthermore, recent experiments and genomic comparisons have demonstrated the role of the same proteins in numerous human neurological diseases. I propose to use forward and reverse genetic approaches in Drosophila to elucidate the cellular and molecular mechanisms underlying neurological diseases such as epilepsy and related disorders that involve aberrant neuronal hyperexcitability.
Aim 1 proposes a reverse genetics approach to study the in vivo role of the KCNQ K+ channel, a regulator of neuronal excitability, which has been directly linked to epilepsy, heart arrhythmia and deafness. The temporal and spatial expression pattern of the KCNQ channel will be determined. A structure-function analysis of the KCNQ channel will be performed by generating various site-directed mutant animals. These KCNQ mutant flies will be characterized behaviorally and physiologically to determine the role of this channel in neuronal signaling, plasticity and neurological disorders.
Aim 2 proposes a forward genetics approach to characterize three novel hyperexcitable mutants with behavioral and physiological seizures followed by paralysis. These affected genes are well mapped and will be identified and cloned. In addition, detailed physiological characterization of muscle and neuronal function will be done to determine the specific mechanisms underlying the behavioral detects in these mutants.
| Fergestad, Tim; Sale, Harinath; Bostwick, Bret et al. (2010) A Drosophila behavioral mutant, down and out (dao), is defective in an essential regulator of Erg potassium channels. Proc Natl Acad Sci U S A 107:5617-21 |
| Fergestad, Tim; Bostwick, Bret; Ganetzky, Barry (2006) Metabolic disruption in Drosophila bang-sensitive seizure mutants. Genetics 173:1357-64 |
| Fergestad, Tim; Ganetzky, Barry; Palladino, Michael J (2006) Neuropathology in Drosophila membrane excitability mutants. Genetics 172:1031-42 |
| Coyle, Ian P; Koh, Young-Ho; Lee, Wyan-Ching Mimi et al. (2004) Nervous wreck, an SH3 adaptor protein that interacts with Wsp, regulates synaptic growth in Drosophila. Neuron 41:521-34 |
