Changes in the number of synaptic AMPARs appears to be an important mechanism that regulates synaptic plasticity. We have shown that postsynaptic perfusion (whole-cell) of the IP3R agonist adenophostin strongly potentiates AMPA receptor-mediated EPSCs. This potentiation is blocked by BAPTA and depends on PDZ-domain interactions, suggesting that intracellular Ca2+ release modulates the function and/or stability of synaptic AMPARs (Maher and Kelly, SFN Abstr. # 923.2, 2001). Since intracellular Ca2+ release leads to an increase in synaptic AMPAR function, then SNARE-dependent exocytosis may be necessary to insert new AMPARs at synapses. To examine the latter postulate, we co-perfused adenophostin plus a recombinant synaptotagmin peptide consisting of tandem C2A domains (C2A-C2A) that inhibits exocytosis in permeabilized PC12 cells (Earles et al., 2001). Co-perfusion of C2A-C2A plus adenophostin strongly attenuated increases in EPSC amplitudes compared to adenophostin alone, suggesting that postsynaptic intra...