Changes in the number of postsynaptic AMPARs occur during synaptic maturation and during rapid and long term changes in synaptic efficacy. As a consequence, the study of how AMPARs are delivered to, endocytosed from and recycled back to the postsynaptic membrane is a major area of interest in the field of synaptic plasticity. To date, phosphorylation of AMPARs has been studied as a well-established posttranslational modification known to contribute to receptor trafficking to and from the postsynaptic membrane. We have recently discovered ubiquitination as a new posttranslational modification that controls the internalization and endocytic sorting of AMPARs. We have identified the E3 ubiquitin ligase Nedd4-1 as a critical enzyme in AMPAR modification by multiple independent biochemical and functional criteria and we have uncovered a previously unsuspected interplay between receptor phosphorylation and ubiquitination. This proposal builds on these new observations linking ubiquitination and phosphorylation in AMPAR trafficking and synaptic function. We will determine the molecular mechanisms and function of AMPAR ubiquitination in neurons by accomplishing these Specific Aims: 1) to determine how synaptic activity regulates AMPAR ubiquitination and determine the relationship between AMPAR phosphorylation and ubiquitination;2) to determine how synaptic activity and the interplay between AMPAR phosphorylation and ubiquitination regulates the trafficking and turnover of AMPARs;and 3) to validate and determine the physiological significance of AMPAR ubiquitination on synaptic function. We expect advancements made in this research to provide new insights into the mechanisms of synaptic plasticity and to lay the groundwork for future studies involving AMPAR trafficking and synaptic dysfunction.

Public Health Relevance

The trafficking of glutamate receptors is a major area of research related to synaptic plasticity and neurodegenerative disease. We have identified that the AMPA-type glutamate receptor (AMPAR) is modified by ubiquitin to control its internalization, endocytic sorting and turnover in neurons. The goal of this proposal is to understand the molecular mechanisms that exist at synapses to regulate AMPAR ubiquitination. To that end, we expect advancements made in this research to provide new insights into the mechanisms of synaptic plasticity and to lay the groundwork for future studies involving AMPAR trafficking and synaptic dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS060847-03
Application #
8286395
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Talley, Edmund M
Project Start
2010-09-01
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$331,209
Indirect Cost
$116,834
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Cifelli, Jessica L; Dozier, Lara; Chung, Tim S et al. (2016) Benzothiazole Amphiphiles Promote the Formation of Dendritic Spines in Primary Hippocampal Neurons. J Biol Chem 291:11981-92
Rodrigues, Elizabeth M; Scudder, Samantha L; Goo, Marisa S et al. (2016) Aβ-Induced Synaptic Alterations Require the E3 Ubiquitin Ligase Nedd4-1. J Neurosci 36:1590-5
Goo, Marisa S; Scudder, Samantha L; Patrick, Gentry N (2015) Ubiquitin-dependent trafficking and turnover of ionotropic glutamate receptors. Front Mol Neurosci 8:60
Scudder, Samantha L; Patrick, Gentry N (2015) Synaptic structure and function are altered by the neddylation inhibitor MLN4924. Mol Cell Neurosci 65:52-7
Scudder, Samantha L; Goo, Marisa S; Cartier, Anna E et al. (2014) Synaptic strength is bidirectionally controlled by opposing activity-dependent regulation of Nedd4-1 and USP8. J Neurosci 34:16637-49
Cartier, Anna E; Ubhi, Kiren; Spencer, Brian et al. (2012) Differential effects of UCHL1 modulation on alpha-synuclein in PD-like models of alpha-synucleinopathy. PLoS One 7:e34713
Schwarz, Lindsay A; Patrick, Gentry N (2012) Ubiquitin-dependent endocytosis, trafficking and turnover of neuronal membrane proteins. Mol Cell Neurosci 49:387-93
Hamilton, Andrew M; Oh, Won Chan; Vega-Ramirez, Hugo et al. (2012) Activity-dependent growth of new dendritic spines is regulated by the proteasome. Neuron 74:1023-30
Djakovic, Stevan N; Marquez-Lona, Esther M; Jakawich, Sonya K et al. (2012) Phosphorylation of Rpt6 regulates synaptic strength in hippocampal neurons. J Neurosci 32:5126-31
Jakawich, S K; Neely, R M; Djakovic, S N et al. (2010) An essential postsynaptic role for the ubiquitin proteasome system in slow homeostatic synaptic plasticity in cultured hippocampal neurons. Neuroscience 171:1016-31

Showing the most recent 10 out of 12 publications