Glial cells play a key role in neuronal development and function. However, the signals exchanged by glialcells and neurons are poorly understood. Increasing evidence supports the notion that ephrins and Ephreceptors play an important role in the interactions between glial cells and neuronal axons as well asdendrites in different parts of the central and peripheral nervous system. We recently discovered a new formof neuron-glia communication that involves the ephrin-A3 ligand expressed on the surface of astrocytes inthe hippocampus and the EphA4 receptor tyrosine kinase expressed on dendritic spines. Dendritic spinesare small protrusions on neuronal dendrites that make synaptic contact with axonal terminals. Typically,mature spines have an enlarged head connected to the dendrite through a narrow neck. Changes in theshape, size and number of dendritic spines in the hippocampus likely contribute to learning and storing longtermmemories. Our evidence suggests that the interplay between ephrin-A3 and EphA4 mediates a form ofrepulsive communication between astrocytes and neurons that counteracts signals promoting theenlargement of spines and prevents distortion and disorganization of the spines. This may represent amechanism regulating spine remodeling during learning and memory formation. Importantly thecommunication likely is bidirectional, with ephrin-A3 also initiating signals that affect the properties ofastrocytes coming in contact with EphA4-positive dendrites. The goal of this project is to evaluate the role ofglial ephrin-A3 in the regulation of dendritic spine development and remodeling and synaptic transmission inhippocampal neurons. Furthermore, we will investigate the signaling pathways mediated by ephrin-A3 andtheir role in astrocyte physiology. Recently obtained ephrin-A3 knockout mice will be important tools toachieve these goals. The proposed research will provide information on whether mutations in the ephrin-A3gene contribute to neurological diseases characterized by abnormalities in dendritic spines includingmental retardation, autism, epilepsy, and schizophrenia and whether the ephrin-A3 knockout mouse mayrepresent a useful neurological disease model. Strategies to manipulate ephrin function in glial cells couldhelp treatment of neurological disorders involving aberrant neuron-glia interactions in the hippocampus andother regions of the nervous system.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD025938-17
Application #
7581048
Study Section
Pediatrics Subcommittee (CHHD)
Project Start
2008-03-01
Project End
2012-02-29
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
17
Fiscal Year
2008
Total Cost
$379,370
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Cattaruzza, Sabrina; Ozerdem, Ugur; Denzel, Martin et al. (2013) Multivalent proteoglycan modulation of FGF mitogenic responses in perivascular cells. Angiogenesis 16:309-27
Tigges, Ulrich; Komatsu, Masanobu; Stallcup, William B (2013) Adventitial pericyte progenitor/mesenchymal stem cells participate in the restenotic response to arterial injury. J Vasc Res 50:134-44
Falivelli, Giulia; Lisabeth, Erika Mathes; Rubio de la Torre, Elena et al. (2013) Attenuation of eph receptor kinase activation in cancer cells by coexpressed ephrin ligands. PLoS One 8:e81445
You, Weon-Kyoo; Bonaldo, Paolo; Stallcup, William B (2012) Collagen VI ablation retards brain tumor progression due to deficits in assembly of the vascular basal lamina. Am J Pathol 180:1145-58
Irie, Fumitoshi; Badie-Mahdavi, Hedieh; Yamaguchi, Yu (2012) Autism-like socio-communicative deficits and stereotypies in mice lacking heparan sulfate. Proc Natl Acad Sci U S A 109:5052-6
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