The Ras superfamily of small GTPase proteins is important for many neuronal processes essential to synaptic plasticity, including long-term synaptic potentiation, formation of new synapses, and regulation of cell excitability. Among the Ras superfamily, a particularly important subfamily is a group of proteins called Rab, which regulate trafficking of membrane and glutamate receptors during synaptic plasticity. Consistent with the importance of Rab signaling in synaptic plasticity, abnormal Rab signaling is associated with diseases causing cognitive impairments and learning deficits. However, the spatiotemporal dynamics of Rab proteins during synaptic plasticity and their exact functions at individual dendritic spines are not fully understood. Thus, the objective of this project is to elucidate the mechanisms and roles of Rab protiens in dendritic spines during synaptic plasticity. We have developed highly sensitive biosensors for imaging activity of Rab4, Rab5, Rab8 and Rab10. Our preliminary data suggest that Rab proteins are activated or inactivated in different temporal windows during synaptic plasticity. Based on these preliminary data and previous literatures, our central hypothesis is that Rab proteins regulate the balance of membrane trafficking between different internal membrane compartments in dendritic spines to regulate functional and structural plasticity of dendritic spines, and this in turn modulates synaptic plasticity, learning and memory. In this project, we will further analyze signaling mediated by Rab proteins and their roles in trafficking of membrane and receptors during synaptic plasticity.
Our specific aims are 1) to reveal the spatiotemporal dynamics of Rab activity during synaptic plasticity and to identify upstream regulators of Rab proteins, 2) to elucidate the roles of Rab proteins in structure and function of spines and in membrane trafficking during synaptic plasticity, 3) to identify the roles of Rab proteins in glutamate receptor internalization and recycling using biochemical assays, and 4) to elucidate the roles of Rab proteins in synaptic plasticity, learning and memory. This work will advance our understanding of how Rab couples calcium with synaptic plasticity, learning and memory.

Public Health Relevance

Synaptic plasticity is regulated by signaling mediated by a group of signaling proteins called small GTPase proteins. Rab proteins are one of the subgroups of these molecules, and play important roles in membrane trafficking required for synaptic plasticity. Several mental diseases are caused by abnormal signaling by these molecules. Our proposed research will improve our knowledge of the biochemical events that underlie Rab signaling and its role in synaptic plasticity, learning and memory, and will hopefully provide significant impact on the therapeutics of Rab-related mental diseases such as Alzheimer?s disease, Parkison disease and mental retardation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH080047-13
Application #
10077359
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Driscoll, Jamie
Project Start
2007-04-05
Project End
2023-12-30
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
13
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Max Planck Florida Corporation
Department
Type
DUNS #
022946007
City
Jupiter
State
FL
Country
United States
Zip Code
33458
Colgan, Lesley A; Hu, Mo; Misler, Jaime A et al. (2018) PKC? integrates spatiotemporally distinct Ca2+ and autocrine BDNF signaling to facilitate synaptic plasticity. Nat Neurosci 21:1027-1037
Nishiyama, Jun; Mikuni, Takayasu; Yasuda, Ryohei (2017) Virus-Mediated Genome Editing via Homology-Directed Repair in Mitotic and Postmitotic Cells in Mammalian Brain. Neuron 96:755-768.e5
Chang, Jui-Yun; Parra-Bueno, Paula; Laviv, Tal et al. (2017) CaMKII Autophosphorylation Is Necessary for Optimal Integration of Ca2+ Signals during LTP Induction, but Not Maintenance. Neuron 94:800-808.e4
Murakoshi, Hideji; Shin, Myung Eun; Parra-Bueno, Paula et al. (2017) Kinetics of Endogenous CaMKII Required for Synaptic Plasticity Revealed by Optogenetic Kinase Inhibitor. Neuron 94:37-47.e5
Tang, Shen; Yasuda, Ryohei (2017) Imaging ERK and PKA Activation in Single Dendritic Spines during Structural Plasticity. Neuron 93:1315-1324.e3
Mikuni, Takayasu; Nishiyama, Jun; Sun, Ye et al. (2016) High-Throughput, High-Resolution Mapping of Protein Localization in Mammalian Brain by In Vivo Genome Editing. Cell 165:1803-1817
Hedrick, Nathan G; Harward, Stephen C; Hall, Charles E et al. (2016) Rho GTPase complementation underlies BDNF-dependent homo- and heterosynaptic plasticity. Nature 538:104-108
Chu, Jun; Oh, Younghee; Sens, Alex et al. (2016) A bright cyan-excitable orange fluorescent protein facilitates dual-emission microscopy and enhances bioluminescence imaging in vivo. Nat Biotechnol 34:760-7
Harward, Stephen C; Hedrick, Nathan G; Hall, Charles E et al. (2016) Autocrine BDNF-TrkB signalling within a single dendritic spine. Nature 538:99-103
Laviv, Tal; Kim, Benjamin B; Chu, Jun et al. (2016) Simultaneous dual-color fluorescence lifetime imaging with novel red-shifted fluorescent proteins. Nat Methods 13:989-992

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