The majority of mature excitatory synapses in the CNS occur on specialized morphologic structures known as dendritic spines, and it is clear from studies in cell culture that the EphB receptor tyrosine kinase and the NMDAR are involved in proper spine and synapse formation. Recent work has also shown that activated EphB can both recruit and modulate the function of NMDARs.
Aim 1 of this proposal will determine the steps of dendritic spine morphogenesis that are regulated by EphB receptor signaling by examining and manipulating neurons over time from EphB null mice.
Aim 2 will assess the ability of activated EphB to recruit NMDARs in a more complex system, cortical slice culture, using fluorescently-tagged receptors and two-photon microscopy. Finally, the known interaction of EphB and NMDARs suggests a coordinated role during the development of dendritic spines;
Aim 3 will directly test for this cooperative activity in cortical slice using pharmacology to manipulate receptor function and two-photon imaging to visualize spine morphology. Increased understanding of these molecular mechanisms is critical in addressing human neurologic diseases whose phenotype include abnormal spine formation, such as Fragile X, Down, and Rett Syndromes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30NS051894-03
Application #
7233124
Study Section
Special Emphasis Panel (ZNS1-SRB-M (13))
Program Officer
Mamounas, Laura
Project Start
2005-06-01
Project End
2008-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
3
Fiscal Year
2007
Total Cost
$29,949
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
Kayser, Matthew S; Nolt, Mark J; Dalva, Matthew B (2008) EphB receptors couple dendritic filopodia motility to synapse formation. Neuron 59:56-69
Kayser, Matthew S; McClelland, Andrew C; Hughes, Ethan G et al. (2006) Intracellular and trans-synaptic regulation of glutamatergic synaptogenesis by EphB receptors. J Neurosci 26:12152-64