DLG4

DLG4 is a gene that encodes PSD-95, also known as SAP90, a major scaffolding protein of the postsynaptic density in excitatory synapses. It is a member of the membrane-associated guanylate kinase (MAGUK) family and plays a central role in assembling and stabilizing signaling complexes at glutamatergic synapses.

The protein architecture of DLG4 includes three PDZ domains, an SH3 domain, and a guanylate kinase-like (GUK) domain. This arrangement equips PSD-95 to bind a range of synaptic proteins and receptors, effectively organizing the postsynaptic membrane and signaling machinery.

In neurons, PSD-95 is concentrated at postsynaptic densities in the forebrain, where it anchors and clusters receptors such as NMDA and AMPA receptors, aligning them with downstream signaling components. It interacts with neuroligins, GKAP/DLGAP proteins, and Shank family members, forming a postsynaptic signaling complex that supports synaptic maturation, maintenance, and plasticity. Through these interactions, DLG4 influences synaptic strength and plasticity, including processes underlying learning and memory.

DLG4 is widely expressed in the brain, with particularly high levels in forebrain regions. Its function as a central organizer of the excitatory synapse makes it a focus of research on synaptic development and neuropsychiatric disorders. Genetic variants and rare mutations in DLG4 have been investigated for associations with autism spectrum disorders and intellectual disability, though the phenotype often reflects a complex genetic background. Animal models lacking DLG4 display deficits in synaptic transmission and long-term potentiation, supporting its critical role in synaptic function. Alternative splicing generates multiple isoforms, adding to functional diversity.