SAP97 directs NMDA receptor spine targeting and synaptic plasticity

SAP97 is a multidomain scaffold protein implicated in the forward trafficking and synaptic localization of NMDA-and AMPA-type glutamate receptors. Alternative splicing of SAP97 transcripts gives rise to palmitoylated aSAP97 and L27-domain containing beta SAP97 isoforms that differentially regulate the subsynaptic localization of GluR1 subunits of AMPA receptors. Here, we examined whether SAP97 isoforms regulate the mechanisms underlying long-term potentiation (LTP) and depression (LTD) and find that both alpha- and beta-forms of SAP97 impair LTP but enhance LTD via independent isoform-specific mechanisms. Live imaging of alpha- and beta SAP97 revealed that the altered synaptic plasticity was not due to activity-dependent changes in SAP97 localization or exchange kinetics. However, by recording from pairs of synaptically coupled hippocampal neurons, we show that alpha SAP97 occludes LTP by enhancing the levels of postsynaptic AMPA receptors, while beta SAP97 blocks LTP by reducing the synaptic localization of NMDA receptors. Examination of the surface pools of AMPA and NMDA receptors indicates that alpha SAP97 selectively regulates the synaptic pool of AMPA receptors, whereas beta SAP97 regulates the extrasynaptic pools of both AMPA and NMDA receptors. Knockdown of beta SAP97 increases the synaptic localization of both AMPA and NMDA receptors, showing that endogenous beta SAP97 restricts glutamate receptor expression at excitatory synapses. This isoform-dependent differential regulation of synaptic versus extrasynaptic pools of glutamate receptors will determine how many receptors are available for the induction and the expression of synaptic plasticity. Our data support a model wherein SAP97 isoforms can regulate the ability of synapses to undergo plasticity by controlling the surface distribution of AMPA and NMDA receptors.