Alternative N-Terminal Domains of PSD-95 and SAP97 Govern Activity-Dependent Regulation of Synaptic AMPA Receptor Function

SummaryPSD-95 and SAP97 are scaffolding proteins that have been implicated in regulating AMPA receptor incorporation and function at synapses. Gain- and loss-of-function approaches, however, have generated conflicting results. To minimize adaptations during development and potential dominant-negative effects of overexpression, we have combined silencing of endogenous PSD-95 in mature neurons with heterologous expression of specific SAP97 or PSD-95 isoforms. We find that both PSD-95 and SAP97 contain alternative N termini expressing either double cysteines that normally are palmitoylated (α-isoforms) or an L27 domain (β-isoforms). Whereas α-isoforms of PSD-95 and SAP97 influence AMPA receptor-mediated synaptic strength independent of activity, the effects of β-isoforms are regulated by activity in a CaMKII-dependent manner. Importantly, the synaptic effects of the β-isoforms are masked by the endogenous α-isoform of PSD-95. These results demonstrate that the different N termini of the predominant endogenous forms of PSD-95 (α-isoform) and SAP97 (β-isoform) govern their role in regulating synaptic function.