Transmission of information within a neural circuit depends on proper development of synaptic connections between neurons and their targets. Understanding how genes and molecular pathways regulate synapse growth and plasticity is crucial to understanding how the nervous system develops and functions properly. Many of the molecular mechanisms that govern synapse structure and function have been uncovered through genetic studies of Drosophila larval neuromuscular junction. Synaptic growth and plasticity requires communication between the motor neuron (pre-synaptic) and muscle (post-synaptic) and involves signaling pathways including Wnt and BMP pathways. However, many aspects of synaptic development are still unknown. In preliminary studies, I have discovered that Tollo, a member of the Toll family of receptors, which is orthologous to vertebrate TLR8, is a positive regulator of NMJ growth and development. The Toll signaling pathway has been well characterized in Drosophila especially with regard to embryonic dorsoventral patterning and the innate immune response, but signaling via Tollo and its role in synaptic development has not been characterized. To unravel the molecular mechanisms of Tollo function in synaptic growth and plasticity, I will genetically identify the upstream and downstream components of the Tollo signaling pathway at the Drosophila NMJ. I will also determine the tissue/cell specific requirements for Tollo expression as well as for its potential ligand(s), to provide a more precise understanding of how Tollo signaling in the nervous system enables communication with target cells and tissues. In addition, I will examine the effect of Tollo on synaptic function via electrophysiological analyses. The work proposed here will provide further insight into the molecular mechanisms of how synaptic development is regulated.
Determining the genes and molecular mechanisms that govern synaptic growth will enhance understanding of synapse formation and function and may also reveal novel insights about how the nervous system communicates with target tissues such as muscle. These studies are of direct medical relevance, as defects in synaptic growth and plasticity are associated with a broad range of neurological disorders including mental retardation, epilepsy, motor, cognitive and psychological impairments, as well as neurodegenerative diseases.
|Ballard, Shannon L; Miller, Daniel L; Ganetzky, Barry (2014) Retrograde neurotrophin signaling through Tollo regulates synaptic growth in Drosophila. J Cell Biol 204:1157-72|