The broad goal of this proposal is to understand mechanisms for synaptic plasticity that may underlie aspects of learning and memory, especially for regulation of glutamate receptors by calcium-dependent protein phosphorylation. Neuronal circuits store information in the brain and the synaptic strength in these neuronal circuits is modified by neuronal activity. Long-term potentiation (LTP) is a well-established model for synaptic plasticity in the brain, that is, brief trains of high frequency stimulation cause an abrupt and sustained increase in the efficacy of synaptic transmission. Excitatory synapses in the brain use glutamate as the major neurotransmitter, and the glutamate signal is mediated by 2 classes of ionotropic glutamate receptors, NMDA-sensitive glutamate receptors and AMPA-sensitive glutamate receptors. During LTP, calcium influx through NMDA receptors increases functional AMPA receptors at synapses through the activation of protein kinases. However, the relevant targets for protein kinases/phosphatases and the downstream mechanisms that enhance synaptic transmission remain unclear. In the past 5 years I have studied the molecular machinery that stabilizes AMPA receptors at synapses and identified transmembrane AMPA receptor regulatory proteins (TARPs) as key molecules. TARPs modulate both trafficking of AMPA receptors to synapses and the gating and pharmacology of the channel at synapses. TARPs are quantitatively phosphorylated in the brain and LTP requires TARPs phosphorylation;thus, TARPs are critical substrates in LTP. We now propose to determine how phosphorylation of TARPs regulates the AMPA receptor trafficking that may underlie synaptic plasticity. We will determine the kinase-specific phosphorylation sites in TARPs that lead to increases in the number of synaptic AMPA receptors. We will also identify molecules that interact with TARPs in a phosphorylation-dependent manner. In addition, we will use genetic approaches to determine how targeted disruption of TARP phosphorylation modulates the synaptic targeting and stability of AMPA receptors. These studies will provide fundamental insights into the mechanisms that regulate synaptic strength at excitatory synapses regards to learning and memory. In addition, these studies will contribute to the development of pharmaceutical drugs as cognition enhancers to treat neurodegenerative disease patients including Alzheimer disease, Parkinson's disease and others.

Public Health Relevance

Neuronal circuits store information in the brain and the synaptic strength in these neuronal circuits is modified by neuronal activity. The broad goal of this proposal is to understand mechanisms for synaptic plasticity that may underlie aspects of learning and memory. These studies will provide fundamental insights into the mechanisms that regulate synaptic strength at excitatory synapses regards to learning and memory. In addition, these studies will contribute to the development of pharmaceutical drugs as cognition enhancers to treat neurodegenerative disease patients including Alzheimer disease, Parkinson's disease and others.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH077939-05
Application #
8288194
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Asanuma, Chiiko
Project Start
2008-08-01
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$368,651
Indirect Cost
$145,901
Name
Yale University
Department
Physiology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Yan, Dan; Yamasaki, Miwako; Straub, Christoph et al. (2013) Homeostatic control of synaptic transmission by distinct glutamate receptors. Neuron 78:687-99
Yan, Dan; Tomita, Susumu (2012) Defined criteria for auxiliary subunits of glutamate receptors. J Physiol 590:21-31
Sumioka, Akio; Brown, Travis E; Kato, Akihiko S et al. (2011) PDZ binding of TARP?-8 controls synaptic transmission but not synaptic plasticity. Nat Neurosci 14:1410-2
Gill, Martin B; Kato, Akihiko S; Roberts, Matthew F et al. (2011) Cornichon-2 modulates AMPA receptor-transmembrane AMPA receptor regulatory protein assembly to dictate gating and pharmacology. J Neurosci 31:6928-38
Kim, Kwang S; Yan, Dan; Tomita, Susumu (2010) Assembly and stoichiometry of the AMPA receptor and transmembrane AMPA receptor regulatory protein complex. J Neurosci 30:1064-72
Kato, Akihiko S; Gill, Martin B; Ho, Michelle T et al. (2010) Hippocampal AMPA receptor gating controlled by both TARP and cornichon proteins. Neuron 68:1082-96
Sumioka, Akio; Yan, Dan; Tomita, Susumu (2010) TARP phosphorylation regulates synaptic AMPA receptors through lipid bilayers. Neuron 66:755-67
Tomita, Susumu (2010) Regulation of ionotropic glutamate receptors by their auxiliary subunits. Physiology (Bethesda) 25:41-9