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 #
2R01NS036715-13A1
Application #
8108369
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
2011-02-01
Budget End
2012-01-31
Support Year
13
Fiscal Year
2011
Total Cost
$514,138
Indirect Cost
Name
Johns Hopkins University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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
Diering, Graham H; Nirujogi, Raja S; Roth, Richard H et al. (2017) Homer1a drives homeostatic scaling-down of excitatory synapses during sleep. Science 355:511-515
Chiu, Shu-Ling; Diering, Graham Hugh; Ye, Bing et al. (2017) GRASP1 Regulates Synaptic Plasticity and Learning through Endosomal Recycling of AMPA Receptors. Neuron 93:1405-1419.e8
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
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
Nomura, J; Jaaro-Peled, H; Lewis, E et al. (2016) Role for neonatal D-serine signaling: prevention of physiological and behavioral deficits in adult Pick1 knockout mice. Mol Psychiatry 21:386-93
Zeng, Menglong; Shang, Yuan; Araki, Yoichi et al. (2016) Phase Transition in Postsynaptic Densities Underlies Formation of Synaptic Complexes and Synaptic Plasticity. Cell 166:1163-1175.e12
Gu, Yi; Chiu, Shu-Ling; Liu, Bian et al. (2016) Differential vesicular sorting of AMPA and GABAA receptors. Proc Natl Acad Sci U S A 113:E922-31
Gu, Yi; Huganir, Richard L (2016) Identification of the SNARE complex mediating the exocytosis of NMDA receptors. Proc Natl Acad Sci U S A 113:12280-12285
Goldschmidt, Hana L; Tu-Sekine, Becky; Volk, Lenora et al. (2016) DGK? Catalytic Activity Is Required for Efficient Recycling of Presynaptic Vesicles at Excitatory Synapses. Cell Rep 14:200-7

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