Synaptic PSD-95 biology: from localization and interactors to N-terminus function

Activity-dependent modifications in synaptic strength, collectively referred to as synaptic plasticity, represent the primary cellular mechanism underlying learning and memory. Synaptic potentiation is mediated by the cellular mechanism known as long-term potentiation (LTP), whereas synaptic weakening occurs via the induction of long-term depression (LTD). In this review, we center on the question of synaptic plasticity from the framework of the postsynaptic density protein-95 (PSD-95) protein. PSD-95 is chosen as a point of discussion due to its critical role in organizing the nanoscale architecture of the postsynaptic density (PSD) and orchestrating key signaling pathways involved in synaptic plasticity, namely N-methyl-d-aspartate receptor (NMDAR)-dependent LTD. We emphasize posttranslational modifications (PTMs) of the N-terminal domain of PSD-95 and their influence on synaptic localization and stability. In particular, we synthesize evidence for phosphorylation-dependent cis-trans isomerization regulating palmitoylation and membrane association. This model integrates nanoscale crowding, PTM gating, and modular protein interaction domains to explain how LTD is locally initiated and maintained at excitatory synapses.