Proper synaptic communication is necessary for normal brain function and information processing, and disrupted synaptic communication is associated with many neurological disorders. AMPA-type glutamate receptors (AMPARs) are critical mediators of synaptic communication, mediating much of the excitatory postsynaptic responses in the brain. AMPARs exist as tetramers of either homogeneous or heterogeneous subunit composition. While the specific subunit composition of an AMPAR can dictate the biophysical properties of the channel, the role of these different subunits in vivo is unclear. It as been hypothesized that learning and memory is encoded by experience-dependent trafficking of AMPARs at synapses in intact neural circuits, yet how prior sensory experience modulates AMPAR trafficking and how changes in AMPAR trafficking in turn modulate synaptic efficacy and underlie behavioral plasticity in the intact animal remains an open question. Using C. elegans forward genetics, my lab has been studying regulators of AMPAR trafficking based on their functional requirements in vivo. Recently we found that AMPARs are recycled through an endosome-to-Golgi retrograde recycling pathway regulated by RAB-6.2 (a Rab6-type GTPase) and the retromer complex. Whereas little is known about Rab6/retromer pathway function in the nervous system, we found that this pathway maintains the synaptic level of specific AMPAR subunit combinations. We found that another Rab6 family member, RAB-6.1, regulates the recycling of a different set of AMPAR subunit combinations. Using yeast two-hybrid, we also identified candidate effectors and a GAP for theses Rabs. In a forward genetic screen, we identified mutants in a new gene that negatively regulates AMPAR retrograde transport, mostly likely by negatively regulating one or both Rab6 protein. We hypothesize that these two Rab6 proteins promote the recycling of distinct AMPAR subunit combinations. We propose that prior sensory experience regulates the balance of these two recycling pathways, which in turn determines which AMPAR subunit composition is localized at the synapse and thus the habituation kinetics at that synapse. We will test this hypothesis through four specific aims. Firs, we will characterize the role of RAB-6.1 in regulating AMPAR recycling. Second, we will characterize the role of TBC-1 as a potential GAP negative regulator of the two Rab6 proteins. Third, we will characterize the role of a new phosphoinositide phosphatase enzyme as a potential Rab6 effector that modulates lipid membrane composition. Fourth, we will clone and characterize the newly identified gene that appears to negatively regulate Rab6 activity and AMPAR retrograde recycling.
These aims will include molecular, cellular, behavioral, biochemical, and electrophysiological analyses, and will provide clues to the mechanisms by which glutamate receptors are regulated.

Public Health Relevance

Deficits in glutamate receptor function, particularly AMPA-type receptors, have been associated with numerous neurological disorders and neurodegenerative diseases, including schizophrenia, depression, traumatic brain injury, ischemic stroke, and ALS. It is critical to understand how glutamate receptors are regulated in order to develop novel applications for the treatment and prevention of brain damage resulting after traumatic injury or stroke, as well as neurological disorders associated with altered glutamate receptor function. In addition, while little is known about the function of the retromer and retrograde recycling in neurons, this pathway has been associated with Alzheimer's Disease (AD), because one of the main causative agents of AD, the Amyloid Precursor Protein (APP), is recycled and processed to beta-amyloid through this same retrograde pathway. A better understanding of retrograde recycling in neurons should allow us to develop new diagnostic and therapeutic approaches for treating and/or preventing AD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS042023-10
Application #
8728517
Study Section
Special Emphasis Panel (ZRG1-MDCN-E (02))
Program Officer
Talley, Edmund M
Project Start
2001-07-01
Project End
2018-12-31
Budget Start
2014-02-01
Budget End
2014-12-31
Support Year
10
Fiscal Year
2014
Total Cost
$368,648
Indirect Cost
$128,098
Name
Rutgers University
Department
None
Type
Organized Research Units
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Zhang, Donglei; Dubey, Jyoti; Koushika, Sandhya P et al. (2016) RAB-6.1 and RAB-6.2 Promote Retrograde Transport in C. elegans. PLoS One 11:e0149314
Park, Eun Chan; Rongo, Christopher (2016) The p38 MAP kinase pathway modulates the hypoxia response and glutamate receptor trafficking in aging neurons. Elife 5:
Joshi, Kishore K; Matlack, Tarmie L; Rongo, Christopher (2016) Dopamine signaling promotes the xenobiotic stress response and protein homeostasis. EMBO J 35:1885-901
Rongo, Christopher (2015) Better to burn out than it is to rust: coordinating cellular redox states during aging and stress. EMBO J 34:2310-1
Ghose, Piya; Park, Eun Chan; Tabakin, Alexandra et al. (2013) Anoxia-reoxygenation regulates mitochondrial dynamics through the hypoxia response pathway, SKN-1/Nrf, and stomatin-like protein STL-1/SLP-2. PLoS Genet 9:e1004063
Rongo, Christopher (2013) Going mobile: AMPA receptors move synapse to synapse in vivo. Neuron 80:1339-41
Park, Eun Chan; Ghose, Piya; Shao, Zhiyong et al. (2012) Hypoxia regulates glutamate receptor trafficking through an HIF-independent mechanism. EMBO J 31:1379-93
Zhang, Donglei; Isack, Nora R; Glodowski, Doreen R et al. (2012) RAB-6.2 and the retromer regulate glutamate receptor recycling through a retrograde pathway. J Cell Biol 196:85-101
Liu, Gang; Rogers, Jason; Murphy, Coleen T et al. (2011) EGF signalling activates the ubiquitin proteasome system to modulate C. elegans lifespan. EMBO J 30:2990-3003
Rongo, Christopher (2011) Epidermal growth factor and aging: a signaling molecule reveals a new eye opening function. Aging (Albany NY) 3:896-905

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