PSD95

PSD-95, or postsynaptic density protein 95, is a major scaffolding protein of the postsynaptic density at glutamatergic synapses in the vertebrate brain. It is encoded by the DLG4 gene. PSD-95 belongs to the membrane-associated guanylate kinase (MAGUK) family and features three PDZ domains, an SH3 domain, and a guanylate kinase–like domain that is catalytically inactive.

The PDZ domains of PSD-95 bind a range of synaptic proteins, enabling it to organize signaling complexes at the postsynaptic density. Key interactions include binding to NMDA receptor NR2 subunits, neuroligins, AMPA receptor auxiliary subunits such as TARPs, and scaffolding proteins like GKAP/SAPAP and Shank family members. Through these interactions, PSD-95 anchors glutamate receptors and signaling enzymes at the synapse and links them to the actin cytoskeleton. The protein is palmitoylated at its N-terminus, which targets and retains it at synapses; its localization is dynamic and regulated by neuronal activity.

Functionally, PSD-95 is central to the assembly and maintenance of postsynaptic signaling complexes, influences receptor trafficking and synaptic strength, and modulates synaptic plasticity such as long-term potentiation. Disruption of PSD-95 alters NMDA receptor function and synaptic transmission in animal models, highlighting its role in synaptic regulation.

PSD-95 is highly expressed in brain regions including the cortex and hippocampus. Because of its pivotal role in organizing excitatory synapses, altered PSD-95 levels or localization have been reported in various neurological and psychiatric conditions, and it is often studied as a potential target to modulate synaptic function.