An inter-tissue feedback signal that couples muscle activity to glutamate receptor trafficking in distal upstream neurons

About This Grant

Communication between neurons occurs via connections called synapses and is mediated by chemical messengers (neurotransmitters) and their receptors (neurotransmitter receptors). Controlling levels of neurotransmitter receptors at synapses controls the intensity of neuronal communication, which is important for learning, memory and cognition. This project studies how a factor secreted from muscle regulates levels of neurotransmitter receptors at synapses in neurons that control movement in the roundworm Caenorhabditis elegans. Although the genes and molecular pathways that regulate neurotransmitter receptors exist in vertebrates like humans, the proposed studies are conducted using roundworms because they have a compact and defined nervous system, are amenable to genetic manipulation, and are transparent, enabling the study of the entire muscle-to-neuron pathway in live, intact animals. Muscles are known to release hundreds of factors during contraction that have impacts on other organs, including the brain, but exactly what these factors are doing at the molecular level is not known. Results from this study will advance our scientific understanding of how muscle releases factors that signal to the brain to control communication between neurons. This research may also identify molecular pathways relevant for understanding the beneficial effects of exercise on learning, memory and cognition. An outreach plan will develop a hands-on lab research module for undergraduates to teach them about the different ways that neurons can communicate with each other and will develop an interactive summer research activity entitled “What do neuroscientists do?” for students from a local public middle school. Additionally, this project will provide opportunities for undergraduates to work on independent research projects in the lab and for graduate students to obtain training in research, teaching and mentoring. Regulation of the levels of AMPA-type glutamate receptors (AMPARs) at synapses controls synaptic signaling strength and is a major mechanism underlying learning and memory. Although much has been learned about the intracellular proteins and mechanisms that regulate AMPAR trafficking and clustering at synapses, less is known about how AMPARs can be controlled by extracellular factors, especially those secreted at a distance from non-neuronal cells. Dr. Juo and his team discovered a novel inter-tissue signal that couples muscle activity with surface levels of GLR-1/AMPARs at synapses in AVA pre-motor interneurons that reside two synaptic layers upstream of the neuromuscular junction (NMJ) in the nematode C. elegans. The team’s preliminary data show that loss of NMJ signaling or loss of muscle contraction triggers a feedback pathway that increases surface levels of GLR-1 at synapses in AVA neurons. This feedback signal is dependent on unc-31/Calcium-dependent Activator of Protein Secretion (CAPS) acting in muscle, the insulin-like peptide INS-27, which is released from muscle, and DAF-2 insulin receptors acting in neurons. The goal of this proposal is to define the molecular mechanisms underlying this intriguing muscle-to-neuron signal by identifying muscle-secreted factors that act with INS-27, the machinery that acts on muscle to regulate the release of these factors, the signaling mechanisms by which DAF-2/insulin receptors mediate the signal in neurons, and the trafficking mechanisms that control surface levels of GLR-1 in neurons. This proposal takes advantage of a defined motor circuit and genetic tools with precise spatial and temporal resolution to identify mechanisms underlying a muscle-to-neuron signal in an intact organism. Understanding how secreted factors regulate synaptic AMPARs at a distance may reveal mechanisms by which extracellular factors control synaptic strength in other systems. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.