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.
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.
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