DESCRIPTION (provided by applicant): Normal brain function requires precise dendritic shape and electical characteristics. Neurons must acquire these properties during initial development and maintain them through life, except under circumstances where functional plasticity is required. The long-term objectives of this project are to understand the role of neuronal activity in regulating dendritic shape and distribution of voltage-gated ion channels. We have developed techniques for following the dendritic development of identified motoneurons during metamorphosis in the genetically-tractable model organism, Drosophila melanogaster, and demonstrated that activity levels influence dendritic development significantly. Neuronal activity and calcium-dependent transduction pathways can be manipulated precisely, both in vivo and in primary cell culture. Specific aims are: 1. To determine how the functional attributes of identified flight motoneurons are modified during metamorposis. Whole-cell current and voltage-clamp techniques will be employed. 2.To determine which forms of voltage-gated potassium and calcium channels are expressed at different stages, their distributions within the motoneuron and their regulation by steroid hormone. Channel expression will be measured by RT- PCR, and distribution determined by forcing the expression of channels tagged with a tetrad-cystiene motif. 3. Characterize the acitivity-dependent regulation of dendritic development. The activity patterns of identified motoneurons will be increased or decreased by driving the expression of modified ion channels and the effect determined with both in vivo and in vitro measurements of growth and function. 4. Determine the role of calcium-dependent signalling pathways. The source and nature of activity-dependent calcium influx will be determined using genetically-encoded calcium indicators, the highly conserved nature of neuronal ion channels and the molecular pathways that regulate developmental processes suggests that basic information derived from this model system will provide insights into human health. Relevance to public health: Normal brain function requires that neurons develop a precise dendritic structure and a defined array of electrical characteristics. Stroke and diseases, such as epilepsy, can result in improper maintenance of these properties. The proposed research seeks to characterize mechanisms that ensure proper development and maintenance of these characteristics.
|Effective start/end date||2/1/07 → 5/31/12|
- National Institutes of Health: $161,017.00
- National Institutes of Health: $162,729.00
- National Institutes of Health: $162,890.00
- National Institutes of Health: $162,811.00
- National Institutes of Health: $37,190.00