Our long-range goals are to determine the roles and regulation of phosphatidylinositol (3, 5)-bis phosphate (PI3,5P2) in neurons. We recently made the unexpected discovery that PI3, 5P2 is a critical upstream regulator of synaptic strength. PI3,5P2 is in very low abundance. Its synthesis requires the lipid kinase PIKfyve and PIKfyve regulators: Vac14 and Fig4. Our studies of mouse mutants, as well as discovery of human patients with mutations in Fig4, establish the general importance of PI3, 5P2 within the nervous system. We recently made two findings that change current knowledge of the roles of the PI3, 5P2 signaling pathway in neurons. First, the Vac14-PIKfyve-Fig4 complex plays an inhibitory role at excitatory synapses, and affects both presynaptic and postsynaptic function. Second, studies shown here strongly suggest that the Vac14-PIKfyve-Fig4 complex, via its role in endomembrane trafficking, plays a critical role in specific forms of synaptic plasticity. In additin, emerging data from us and others indicate that PI3, 5P2 is a critical upstream regulator of multiple pathways both in neurons and other cell- types. Here we focus on the requirement of PIKfyve, Vac14 and Fig4 for chemical long-term depression and homeostatic down scaling. In addition, in collaboration with Dr. Haoxing Xu (U. Michigan) we have developed a fluorescent probe for PI3,5P2. We anticipate that this probe will greatly expand the ability of us and others to study PI3,5P2 in neurons. The overall goals of this proposal are to 1) Determine whether PI3, 5P2 and PI5P are essential for specific forms of synaptic plasticity. 2) Determine whether calcium is required for the transient activation of PIKfyve, and whether PIKfyve and/or AMPA receptor localization changes during this activation. These proposed studies have the potential to provide significant advances in current knowledge of the molecular basis of synaptic plasticity, as well as advance understanding of molecular mechanisms required for learning and memory.
We recently discovered that the PI3, 5P2 lipid signaling pathway has roles at excitatory synapses. The proposed studies on how PI3, 5P2 modulates synaptic activity, are likely to advance current knowledge of mechanisms of synaptic plasticity. Moreover, they have the potential to establish new insights into learning and memory, as well as insights into selected neuropsychiatric disorders.
|McCartney, Amber J; Zhang, Yanling; Weisman, Lois S (2014) Phosphatidylinositol 3,5-bisphosphate: low abundance, high significance. Bioessays 36:52-64|
|McCartney, Amber J; Zolov, Sergey N; Kauffman, Emily J et al. (2014) Activity-dependent PI(3,5)P2 synthesis controls AMPA receptor trafficking during synaptic depression. Proc Natl Acad Sci U S A 111:E4896-905|
|Samie, Mohammad; Wang, Xiang; Zhang, Xiaoli et al. (2013) A TRP channel in the lysosome regulates large particle phagocytosis via focal exocytosis. Dev Cell 26:511-24|
|Bridges, Dave; Fisher, Kaleigh; Zolov, Sergey N et al. (2012) Rab5 proteins regulate activation and localization of target of rapamycin complex 1. J Biol Chem 287:20913-21|
|Lenk, Guy M; Ferguson, Cole J; Chow, Clement Y et al. (2011) Pathogenic mechanism of the FIG4 mutation responsible for Charcot-Marie-Tooth disease CMT4J. PLoS Genet 7:e1002104|
|Vaccari, Ilaria; Dina, Giorgia; Tronchere, Helene et al. (2011) Genetic interaction between MTMR2 and FIG4 phospholipid phosphatases involved in Charcot-Marie-Tooth neuropathies. PLoS Genet 7:e1002319|
|Chow, Clement Y; Landers, John E; Bergren, Sarah K et al. (2009) Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS. Am J Hum Genet 84:85-8|