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The Journal of Neuroscience, February 22, 2006, 26(8):2343-2357; doi:10.1523/JNEUROSCI.5247-05.2006
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Development/Plasticity/Repair
Transsynaptic Signaling by Postsynaptic Synapse-Associated Protein 97
Maria Paz Regalado, Ryan T. Terry-Lorenzo, Clarissa L. Waites, Craig C. Garner, andRobert C. Malenka Department of Psychiatry and Behavioral Sciences, Nancy Pritzker Laboratory, Stanford University, Palo Alto, California 94304-5485
Correspondence should be addressed to Robert C. Malenka, Department of Psychiatry and Behavioral Sciences, Stanford Medical Center, 1201 Welch Road, Palo Alto, CA 94304-5485. Email: malenka{at}stanford.edu
The molecular mechanisms by which postsynaptic modifications lead to precisely coordinated changes in presynaptic structure and function are primarily unknown. To address this issue, we examined the presynaptic consequences of postsynaptic expression of members of the membrane-associated guanylate kinase family of synaptic scaffolding proteins. Postsynaptic expression of synapse-associated protein 97 (SAP97) increased presynaptic protein content and active zone size to a greater extent than comparable amounts of postsynaptic PSD-95 (postsynaptic density-95) or SAP102. In addition, postsynaptic expression of SAP97 enhanced presynaptic function, as measured by increased FM4-64 dye uptake. The structural presynaptic effects of postsynaptic SAP97 required ligand binding through two of its PDZ (PSD-95/Discs large/zona occludens-1) domains as well as intact N-terminal and guanylate kinase domains. Expression of SAP97 recruited a complex of additional postsynaptic proteins to synapses including glutamate receptor 1, Shank1a, SPAR (spine-associated RapGAP), and proSAP2. Furthermore, inhibition of several different transsynaptic signaling proteins including cadherins, integrins, and EphB receptor/ephrinB significantly reduced the presynaptic growth caused by postsynaptic SAP97. These results suggest that SAP97 may play a central role in the coordinated growth of synapses during development and plasticity by recruiting a complex of postsynaptic proteins that enhances presynaptic terminal growth and function via multiple transsynaptic molecular interactions.
Key words: synapse; active zone; retrograde signal; scaffolding proteins; cell adhesion; PSD-95
Received Nov. 1, 2005; revised Jan. 13, 2006; accepted Jan. 14, 2006.
Correspondence should be addressed to Robert C. Malenka, Department of Psychiatry and Behavioral Sciences, Stanford Medical Center, 1201 Welch Road, Palo Alto, CA 94304-5485. Email: malenka{at}stanford.edu
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