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The Journal of Neuroscience, May 9, 2007, 27(19):5127-5138; doi:10.1523/JNEUROSCI.1170-07.2007

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Cellular/Molecular
EphA4 Signaling Regulates Phospholipase C1 Activation, Cofilin Membrane Association, and Dendritic Spine Morphology

Lei Zhou,¹ Sarah J. Martinez,¹ Michael Haber,¹ Emma V. Jones,¹ David Bouvier,² Guy Doucet,² Amadou T. Corera,³ Edward A. Fon,³ Andreas H. Zisch,^4,5 and Keith K. Murai¹

¹Center for Research in Neuroscience, Department of Neurology and Neurosurgery, The Research Institute of the McGill University Health Center, Montreal General Hospital, Montreal, Quebec, Canada H3G 1A4, ²Département de Pathologie et Biologie Cellulaire and Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montréal, Québec, Canada H3C 3J7, ³Center for Neuronal Survival and Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 3B4, ⁴Department of Obstetrics, University Hospital Zurich, 8091 Zurich, Switzerland, and ⁵Center for Integrative Human Physiology, University of Zurich, 8091 Zurich, Switzerland

Correspondence should be addressed to Dr. Keith K. Murai, Centre for Research in Neuroscience, Montreal General Hospital, 1650 Cedar Avenue L7-212, Montreal, Quebec, Canada H3G 1A4. Email: keith.murai{at}mcgill.ca

Specialized postsynaptic structures known as dendritic spines are the primary sites of glutamatergic innervation at synapses of the CNS. Previous studies have shown that spines rapidly remodel their actin cytoskeleton to modify their shape and this has been associated with changes in synaptic physiology. However, the receptors and signaling intermediates that restructure the actin network in spines are only beginning to be identified. We reported previously that the EphA4 receptor tyrosine kinase regulates spine morphology. However, the signaling pathways downstream of EphA4 that induce spine retraction on ephrin ligand binding remain poorly understood. Here, we demonstrate that ephrin stimulation of EphA4 leads to the recruitment and activation of phospholipase C1 (PLC1) in heterologous cells and in hippocampal slices. This interaction occurs through an Src homology 2 domain of PLC1 and requires the EphA4 juxtamembrane tyrosines. In the brain, PLC1 is found in multiple compartments of synaptosomes and is readily found in postsynaptic density fractions. Consistent with this, PLC activity is required for the maintenance of spine morphology and ephrin-induced spine retraction. Remarkably, EphA4 and PLC activity modulate the association of the actin depolymerizing/severing factor cofilin with the plasma membrane. Because cofilin has been implicated previously in the structural plasticity of spines, this signaling may enable cofilin to depolymerize actin filaments and restructure spines at sites of ephrin–EphA4 contact.

Key words: synapse; plasticity; actin; hippocampus; neuron glia; phosphorylation

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Received Aug. 1, 2006; revised April 4, 2007; accepted April 6, 2007.

Correspondence should be addressed to Dr. Keith K. Murai, Centre for Research in Neuroscience, Montreal General Hospital, 1650 Cedar Avenue L7-212, Montreal, Quebec, Canada H3G 1A4. Email: keith.murai{at}mcgill.ca

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