Glutamate is the major excitatory neurotransmitter in the brain. Activity-dependent changes in the abundance of AMPA-type glutamate receptors (GluRs) at synapses can alter synaptic strength and are a major cellular mechanism involved in learning and memory. Aberrant regulation of GluRs contributes to excitotoxic cell death in ischemia, stroke and several neurodegenerative disorders. Thus it is important to understand the cell biological and molecular mechanisms involved in regulating GluR localization and abundance at synapses. The long-term goal of this research is to define genes and mechanisms that regulate the abundance of GluRs at synapses. Great progress has been made in our understanding of the mechanisms involved in AMPAR insertion (exocytosis) and removal (endocytosis) at synapses. However, much less is known about the motors and adaptors that regulate anterograde trafficking of GluRs from the cell body to the synapse. The focus of this proposal is to understand the fundamental mechanisms involved in regulating motor-dependent transport of GluRs from cell bodies to synapses. We use C. elegans as a genetic model to study genes and mechanisms that regulate the trafficking of GluRs in vivo. We recently showed that the protein kinase CDK-5 promotes anterograde trafficking of GLR-1, a C. elegans GluR, and that the kinesin 3 motor KLP-4/KIF13 is required for this effect. In preliminary studies, we identify two microRNAs (miR-75 and miR-79), and the AP2 clathrin adaptin subunit APM-2/?2, as novel regulators of GLR-1 anterograde transport. We also discovered that GLR-1 stability may be coupled to KLP-4-dependent anterograde transport. In this proposal, Aim 1 will investigate a novel function for APM-2/?2 in the anterograde trafficking of GluRs.
Aim 2 will investigate mechanisms by which the kinase CDK-5 and microRNAs regulate KLP-4-dependent trafficking.
Aim 3 will investigate mechanisms that couple KLP-4-dependent anterograde transport to GLR- 1 degradation. Identifying genes and mechanisms that regulate GluR levels at synapses may provide potential therapeutic targets for reducing GluR-mediated excitotoxicity after stroke and ischemia.

Public Health Relevance

Aberrant function and localization of glutamate neurotransmitter receptors contributes to excitotoxic cell death in ischemia and stroke, and is implicated in several neurological diseases such as Alzheimer's, depression and epilepsy. Our research is focused on defining genes and fundamental mechanisms involved in regulating motor-dependent trafficking of glutamate receptors, which may lead to the development of new therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56NS059953-06
Application #
8678130
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Talley, Edmund M
Project Start
2007-08-15
Project End
2014-06-30
Budget Start
2013-07-15
Budget End
2014-06-30
Support Year
6
Fiscal Year
2013
Total Cost
$412,500
Indirect Cost
$162,500
Name
Tufts University
Department
None
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111