The targeting of neurotransmitter receptors to synapses is essential for efficient synaptic transmission and plays an important role in the regulation of synaptic plasticity in the brain. We have identified several PDZ domain-containing proteins that specifically interact with AMPA receptors, the major excitatory neurotransmitter receptors in the central nervous system. These AMPA receptor interacting proteins are critical for the regulation of the membrane trafficking of AMPA receptors and synaptic plasticity. Several of these proteins, including GRIP1 and GRIP2 (Glutamate Receptor Interacting Proteins) and PICK1 (Protein Interactor with C Kinase), specifically interact with the C-terminal domains of the AMPA receptor GluR 2, 3 and 4c subunits. In addition, we have found that these interactions are dynamically regulated by protein phosphorylation of the receptor subunits. In this research proposal we plan to use several complementary approaches to further characterize the structure and function of PICK1 and GRIP1/2 and determine their roles in AMPA receptor synaptic targeting, synaptic plasticity and behavior. First, we have identified several novel proteins that interact with PICK1 and GRIP1/2 to form PDZ domain-based receptor complexes. We will establish the roles of these new PICK1/GRIP interacting proteins, several of which are implicated in neuropsychiatric diseases, in the regulation of AMPA receptor trafficking, synaptic transmission and plasticity. Second, we will determine how both phosphorylation and a novel regulatory mechanism, palmitoylation, dynamically regulate the PDZ domain- based receptor complex, and how these processes regulate receptor trafficking and synaptic plasticity. In complementary experiments, we will use PICK1 and GRIP1/2 knockout mice, phosphorylation site mutant knockin mice, and knockout mice of selected PICK1 and GRIP1/2 interacting proteins to elucidate the role of PDZ domain-based receptor complexes in several forms of plasticity in the hippocampus, cerebellum, somatosensory cortex and the amygdala. Finally, we will analyze behavioral phenotypes, including spatial and motor learning and fear conditioning and extinction of these knockout and knockin mice to determine the role of these regulatory mechanisms in higher brain processes.

Public Health Relevance

This research will elucidate basic molecular mechanisms that regulate synaptic transmission and plasticity in the brain but it also has broad relevance for many neurological and psychiatric diseases. Dysfunction of synaptic transmission and synaptic plasticity underlies many neurological and psychiatric disorders. This research may therefore reveal novel targets for the development of therapeutic treatments for several brain disorders including pain, drug addiction, schizophrenia, autism, and Alzheimer's and Parkinson's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS036715-14
Application #
8217089
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Whittemore, Vicky R
Project Start
1997-08-01
Project End
2016-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
14
Fiscal Year
2012
Total Cost
$514,138
Indirect Cost
$200,639
Name
Johns Hopkins University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Barber, Casey N; Huganir, Richard L; Raben, Daniel M (2018) Phosphatidic acid-producing enzymes regulating the synaptic vesicle cycle: Role for PLD? Adv Biol Regul 67:141-147
Zhang, Lei; Zhang, Peng; Wang, Guangfu et al. (2018) Ras and Rap Signal Bidirectional Synaptic Plasticity via Distinct Subcellular Microdomains. Neuron 98:783-800.e4
Lin, Edward Y S; Silvian, Laura F; Marcotte, Douglas J et al. (2018) Potent PDZ-Domain PICK1 Inhibitors that Modulate Amyloid Beta-Mediated Synaptic Dysfunction. Sci Rep 8:13438
Heo, Seok; Diering, Graham H; Na, Chan Hyun et al. (2018) Identification of long-lived synaptic proteins by proteomic analysis of synaptosome protein turnover. Proc Natl Acad Sci U S A 115:E3827-E3836
Diering, Graham H; Huganir, Richard L (2018) The AMPA Receptor Code of Synaptic Plasticity. Neuron 100:314-329
Chen, Chih-Ming; Orefice, Lauren L; Chiu, Shu-Ling et al. (2017) Wnt5a is essential for hippocampal dendritic maintenance and spatial learning and memory in adult mice. Proc Natl Acad Sci U S A 114:E619-E628
Lagerlöf, Olof; Hart, Gerald W; Huganir, Richard L (2017) O-GlcNAc transferase regulates excitatory synapse maturity. Proc Natl Acad Sci U S A 114:1684-1689
Lim, Chae-Seok; Kang, Xi; Mirabella, Vincent et al. (2017) BRaf signaling principles unveiled by large-scale human mutation analysis with a rapid lentivirus-based gene replacement method. Genes Dev 31:537-552
Song, Qian; Zheng, Hong-Wei; Li, Xu-Hui et al. (2017) Selective Phosphorylation of AMPA Receptor Contributes to the Network of Long-Term Potentiation in the Anterior Cingulate Cortex. J Neurosci 37:8534-8548
Wang, Qiang; Chiu, Shu-Ling; Koropouli, Eleftheria et al. (2017) Neuropilin-2/PlexinA3 Receptors Associate with GluA1 and Mediate Sema3F-Dependent Homeostatic Scaling in Cortical Neurons. Neuron 96:1084-1098.e7

Showing the most recent 10 out of 89 publications