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The Journal of Neuroscience, June 11, 2008, 28(24):6079-6091; doi:10.1523/JNEUROSCI.1170-08.2008

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Cellular/Molecular
Coordination of Synaptic Adhesion with Dendritic Spine Remodeling by AF-6 and Kalirin-7

Zhong Xie,¹ Huzefa Photowala,¹ Michael E. Cahill,¹ Deepak P. Srivastava,¹ Kevin M. Woolfrey,¹ Cassandra Y. Shum,¹ Richard L. Huganir,² and Peter Penzes¹

¹Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, and ²Department of Neuroscience and Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Correspondence should be addressed to Peter Penzes, Department of Physiology, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Chicago, IL 60611. Email: p-penzes{at}northwestern.edu

Remodeling of central excitatory synapses is crucial for synapse maturation and plasticity, and contributes to neurodevelopmental and psychiatric disorders. Remodeling of dendritic spines and the associated synapses has been postulated to require the coordination of adhesion with spine morphology and stability; however, the molecular mechanisms that functionally link adhesion molecules with regulators of dendritic spine morphology are mostly unknown. Here, we report that spine size and N-cadherin content are tightly coordinated. In rat mature cortical pyramidal neurons, N-cadherin-dependent adhesion modulates the morphology of existing spines by recruiting the Rac1 guanine-nucleotide exchange factor kalirin-7 to synapses through the scaffolding protein AF-6/afadin. In pyramidal neurons, N-cadherin, AF-6, and kalirin-7 colocalize at synapses and participate in the same multiprotein complexes. N-cadherin clustering promotes the reciprocal interaction and recruitment of N-cadherin, AF-6, and kalirin-7, increasing the content of Rac1 and in spines and PAK (p21-activated kinase) phosphorylation. N-cadherin-dependent spine enlargement requires AF-6 and kalirin-7 function. Conversely, disruption of N-cadherin leads to thin, long spines, with reduced Rac1 contact, caused by uncoupling of N-cadherin, AF-6, and kalirin-7 from each other. By dynamically linking N-cadherin with a regulator of spine plasticity, this pathway allows synaptic adhesion molecules to rapidly coordinate spine remodeling associated with synapse maturation and plasticity. This study hence identifies a novel mechanism whereby cadherins, a major class of synaptic adhesion molecules, signal to the actin cytoskeleton to control the morphology of dendritic spines, and outlines a mechanism that underlies the coordination of synaptic adhesion with spine morphology.

Key words: Rac1; GluR1; postsynaptic density; synaptic plasticity; cytoskeleton; synapse

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Received Dec. 18, 2007; revised May 1, 2008; accepted May 2, 2008.

Correspondence should be addressed to Peter Penzes, Department of Physiology, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Chicago, IL 60611. Email: p-penzes{at}northwestern.edu

This article has been cited by other articles:

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