Addition, anxiety, neuropathic pain and Alzheimer's disease have each been shown to share some important common features such as changes in synapse number and defectives regulation of the function or localization of the NMDAR. Remarkably EphB and ephrin-B proteins appear to be important candidate genes in the control of these events during development, in the mature brain, and in these diverse diseases. Yet, our understanding of the mechanisms by which ephrin-Bs and EphB control the events even under normal conditions is rudimentary. Therefore we will focus on two issues (1) how the EphB receptor regulates NMDAR localization and function at synapses and (2) how neurons control the number of synapses they receive. To answer these questions we propose three specific aims: 1. Determine whether a specific domain in EphB2 is necessary and sufficient to control the EphB-NMDAR interaction. 2. Determine whether a specific domain in NR1 is necessary to control the EphB-NMDAR interaction. 3. Determine the molecular mechanisms mediating ephrin-B3 dependent control of synapse density Results from our experiments will provide fundamental insights into mechanisms that control and specify the formation and function of synaptic connections within the brain. In addition, given that EphB/ephrinB can mediate synaptic and structural plasticity, that their expression is regulated by drugs of abuse, and EphBs regulation of NMDAR function has been linked to opiate addiction, our studies will advance understanding of drug-induced pathology and will likely have broad impact on human health.

Public Health Relevance

Defects in synaptic structure and function are often associated with developmental disorders and diseases such as addiction, autism, neuropathic pain, and Alzheimer's. By defining basic mechanisms controlling synapse density and NMDAR synaptic localization, our proposed research will promote understanding of the molecular and cellular mechanisms that mediate these events and should provide new insights into the pathology of and potential therapies for disease such as addiction.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Synapses, Cytoskeleton and Trafficking Study Section (SYN)
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Wu, Da-Yu
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Thomas Jefferson University
Schools of Medicine
United States
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Sheffler-Collins, Sean I; Dalva, Matthew B (2012) EphBs: an integral link between synaptic function and synaptopathies. Trends Neurosci 35:293-304
Kayser, Matthew S; Lee, Anderson C; Hruska, Martin et al. (2011) Preferential control of basal dendritic protrusions by EphB2. PLoS One 6:e17417
Nolt, Mark J; Lin, Ying; Hruska, Martin et al. (2011) EphB controls NMDA receptor function and synaptic targeting in a subunit-specific manner. J Neurosci 31:5353-64
McClelland, Andrew C; Hruska, Martin; Coenen, Andrew J et al. (2010) Trans-synaptic EphB2-ephrin-B3 interaction regulates excitatory synapse density by inhibition of postsynaptic MAPK signaling. Proc Natl Acad Sci U S A 107:8830-5
Dalva, Matthew B (2010) Remodeling of inhibitory synaptic connections in developing ferret visual cortex. Neural Dev 5:5
Dalva, Matthew B (2010) Ephecting excitatory synapse development. Cell 143:341-2
Antion, Marcia D; Christie, Louisa A; Bond, Allison M et al. (2010) Ephrin-B3 regulates glutamate receptor signaling at hippocampal synapses. Mol Cell Neurosci 45:378-88
McClelland, Andrew C; Sheffler-Collins, Sean I; Kayser, Matthew S et al. (2009) Ephrin-B1 and ephrin-B2 mediate EphB-dependent presynaptic development via syntenin-1. Proc Natl Acad Sci U S A 106:20487-92
Dalva, Matthew B (2009) Neuronal activity moves protein palmitoylation into the synapse. J Cell Biol 186:7-9
Kayser, Matthew S; Nolt, Mark J; Dalva, Matthew B (2008) EphB receptors couple dendritic filopodia motility to synapse formation. Neuron 59:56-69

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