Integrin signaling through Arg kinase regulates synapse and dendrite stabilization. Synapses in the human brain must be actively maintained over extended periods of time to ensure the efficacy of neuronal transmission and overall brain function. The failure to properly maintain synapses is thought to contribute to age-related cognitive decline and the pathology of numerous neurodegenerative disorders such as Alzheimer's disease. Understanding the mechanisms of synaptic maintenance may lead to new therapeutic approaches to reduce synapse loss and may identify risk factors for age- and disease-related neurodegeneration. Recent research has identified a pathway involving the Arg tyrosine kinase that is essential for synapse and dendrite maintenance. The overall aim of this project is to identify what upstream signals regulate Arg activity at the synapse and determine what effects those signals have on synapse and dendrite stability. Previous studies in non-neuronal cells have demonstrated that integrins, which are receptors for extracellular matrix components, signal through Arg to coordinate adhesion and cytoskeletal dynamics. This project will test the hypothesis that an integrin/Arg interaction promotes synapse stability in vivo. Hippocampal synapses will be quantified in crosses between arg and integrin?1 mutant mice at different ages via electron microscopy. As Arg activity also regulates dendritic stability, dendritic arbors will be reconstructed in mutant mice by dye-filling live hippocampal neurons. The experiments outlined in this proposal will also determine if integrins signal through Arg kinase by biochemically measuring the relative activity of known Arg substrates in integrin?1 mutant mice. Finally, this project aims to determine the behavioral relevance of the putative integrin/Arg interaction by measuring overall hippocampal function in mutant mice through a novel object recognition task. Through complementary use of genetic, biochemical, and behavioral techniques, this project seeks to identify and characterize an integrin-dependent signaling cascade that promotes synapse and dendrite maintenance. The long-term goal of this line of research is to fully understand what mechanisms stabilize synapses in vivo.

Public Health Relevance

Integrin signaling through Arg kinase regulates synapse and dendrite stabilization Age- and disease-related neurodegeneration extracts an immense personal, social, and economic burden worldwide. As the loss of synapses, which are the connections between neurons, is a common pathology in many forms of neurodegeneration, therapeutic interventions that artificially stabilize synapses may have wide- ranging applications. This project will characterize a novel biochemical mechanism that promotes synapse stability in an effort to identify new therapeutic targets.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F03A-F (20))
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Wise, Bradley C
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Yale University
Schools of Medicine
New Haven
United States
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Warren, M Sloan; Bradley, William D; Gourley, Shannon L et al. (2012) Integrin ?1 signals through Arg to regulate postnatal dendritic arborization, synapse density, and behavior. J Neurosci 32:2824-34