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.