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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS064015-06A1
Application #
8768515
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Gubitz, Amelie
Project Start
2009-01-01
Project End
2019-04-30
Budget Start
2014-07-01
Budget End
2015-04-30
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Pappas, Samuel S; Bonifacino, Juan; Danek, Adrian et al. (2017) Eighth International Chorea-Acanthocytosis Symposium: Summary of Workshop Discussion and Action Points. Tremor Other Hyperkinet Mov (N Y) 7:428
Al-Ramahi, Ismael; Giridharan, Sai Srinivas Panapakkam; Chen, Yu-Chi et al. (2017) Inhibition of PIP4K? ameliorates the pathological effects of mutant huntingtin protein. Elife 6:
Lang, Michael J; Strunk, Bethany S; Azad, Nadia et al. (2017) An intramolecular interaction within the lipid kinase Fab1 regulates cellular phosphatidylinositol 3,5-bisphosphate lipid levels. Mol Biol Cell 28:858-864
Jin, Natsuko; Jin, Yui; Weisman, Lois S (2017) Early protection to stress mediated by CDK-dependent PI3,5P2 signaling from the vacuole/lysosome. J Cell Biol 216:2075-2090
Hasegawa, Junya; Strunk, Bethany S; Weisman, Lois S (2017) PI5P and PI(3,5)P2: Minor, but Essential Phosphoinositides. Cell Struct Funct 42:49-60
Kim, Seong M; Roy, Saurabh G; Chen, Bin et al. (2016) Targeting cancer metabolism by simultaneously disrupting parallel nutrient access pathways. J Clin Invest 126:4088-4102
Jin, Natsuko; Lang, Michael J; Weisman, Lois S (2016) Phosphatidylinositol 3,5-bisphosphate: regulation of cellular events in space and time. Biochem Soc Trans 44:177-84
Hertz, Daniel L; Owzar, Kouros; Lessans, Sherrie et al. (2016) Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism that Increases Risk of Docetaxel-Induced Neuropathy. Clin Cancer Res 22:4890-4900
Jin, Yui; Strunk, Bethany S; Weisman, Lois S (2015) Close encounters of the lysosome-peroxisome kind. Cell 161:197-8

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