Synapses are the junctions through which neurons communicate with each other and transmit signals that control our development, movements and cognitive abilities. An understanding of the molecular steps involved in the development of synapses in the brain is critical for an understanding of disorders of human cognition that may arise when the processes of synapse formation, maintenance and refinement go awry. However, due to the complexity of the temporal and spatial orchestration of the many components of synapses, it has been difficult to distinguish specific steps in the process and to analyze the individual contributions of specific molecules. Our laboratory has shown that members of the EphB family of receptor tyrosine kinases and their ephrinB ligands are involved in the clustering of specific molecules at the excitatory synapse that result in calcium influx leading to depolarization. However, the molecular mechanisms by which these receptor/ligand complexes promote their effect remain unclear. The objectives of this proposal are use a chemical genetic approach to gain a better understanding of the mechanisms by which EphB/ephrinB signaling controls synapse development. To this end, we have generated a mouse strain with knock-in mutations in the kinase domains of all three EphBs that allows for precise temporal control of the kinase activities of the receptors. Using these mice, we can distinguish between the kinase-dependent and kinase-independent events that occur at the synapse. We have also identified a guanine nucleotide exchange factor that is activated by EphB/ephrinB signaling. We propose to analyze the role of this downstream effector in the formation of synapses and in spine development. For these studies, we propose the following two Specific Aims: 1) To characterize the mechanisms by which the EphB receptor tyrosine kinase regulates excitatory synapse formation, maturation and plasticity;2) To study the role of a novel guanine nucleotide exchange factor Ephexin5 in EphB-dependent synapse development and maturation. These studies have the potential to not only provide insights into the molecular events that shape synapse development, but also how the dysfunction of these events may lead to diseases of human cognition.During mammalian development, synaptic activity shapes the formation and maintenance of the trillions of neuronal connections that constitute the circuitry of the brain. Many disorders of human cognition including autism, epilepsy and neurodegenerative diseases are caused by defects in the molecular events that regulate the formation, maintenance and refinement of synapses. An understanding of the molecular steps that control synapse development will provide insights into how their dysregulation gives rise to a disease of human cognitive function, and may ultimately suggest therapies for treatment and/or prevention of these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045500-26
Application #
8204902
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Mamounas, Laura
Project Start
1986-12-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
26
Fiscal Year
2012
Total Cost
$540,986
Indirect Cost
$221,820
Name
Harvard University
Department
Biology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Robichaux, Michael A; Chenaux, George; Ho, Hsin-Yi Henry et al. (2014) EphB receptor forward signaling regulates area-specific reciprocal thalamic and cortical axon pathfinding. Proc Natl Acad Sci U S A 111:2188-93
Veeramah, Krishna R; Johnstone, Laurel; Karafet, Tatiana M et al. (2013) Exome sequencing reveals new causal mutations in children with epileptic encephalopathies. Epilepsia 54:1270-81
Ho, Hsin-Yi Henry; Susman, Michael W; Bikoff, Jay B et al. (2012) Wnt5a-Ror-Dishevelled signaling constitutes a core developmental pathway that controls tissue morphogenesis. Proc Natl Acad Sci U S A 109:4044-51
Wills, Zachary P; Mandel-Brehm, Caleigh; Mardinly, Alan R et al. (2012) The nogo receptor family restricts synapse number in the developing hippocampus. Neuron 73:466-81
Margolis, Seth S; Salogiannis, John; Lipton, David M et al. (2010) EphB-mediated degradation of the RhoA GEF Ephexin5 relieves a developmental brake on excitatory synapse formation. Cell 143:442-55
Siegel, Gabriele; Obernosterer, Gregor; Fiore, Roberto et al. (2009) A functional screen implicates microRNA-138-dependent regulation of the depalmitoylation enzyme APT1 in dendritic spine morphogenesis. Nat Cell Biol 11:705-16
Fu, Wing-Yu; Chen, Yu; Sahin, Mustafa et al. (2007) Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism. Nat Neurosci 10:67-76
Paradis, Suzanne; Harrar, Dana B; Lin, Yingxi et al. (2007) An RNAi-based approach identifies molecules required for glutamatergic and GABAergic synapse development. Neuron 53:217-32
Zhou, Pengcheng; Porcionatto, Marimelia; Pilapil, Mariecel et al. (2007) Polarized signaling endosomes coordinate BDNF-induced chemotaxis of cerebellar precursors. Neuron 55:53-68
Tolias, Kimberley F; Bikoff, Jay B; Kane, Christina G et al. (2007) The Rac1 guanine nucleotide exchange factor Tiam1 mediates EphB receptor-dependent dendritic spine development. Proc Natl Acad Sci U S A 104:7265-70

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