SAP102

SAP102, or DLG2, is a synapse-associated protein that serves as a scaffold at excitatory synapses in the brain. It belongs to the membrane-associated guanylate kinase (MAGUK) family and localizes to the postsynaptic density, where it helps organize signaling complexes essential for synaptic function. SAP102 is expressed broadly in the cortex and hippocampus, with higher levels during early development and a gradual shift toward mature patterns in adulthood.

Structure and interactions: SAP102 contains three PDZ domains, an SH3 domain, and a guanylate kinase (GUK)-like domain, typical of MAGUK proteins. Through its PDZ motifs, it binds NMDA receptor subunits NR2A and NR2B and links them to other scaffold proteins such as GKAP and Shank family members. This network of interactions helps assemble and stabilize receptors, channels, and signaling proteins at the postsynaptic density.

Function and development: As a scaffold, SAP102 coordinates receptor trafficking and synaptic signaling, contributing to the formation, maturation, and plasticity of glutamatergic synapses. Its developmental expression pattern aligns with periods of synaptogenesis and circuit refinement, and while it remains present in mature synapses, its levels can decline relative to other MAGUKs.

Clinical relevance: Variants in the DLG2 gene have been associated with neurodevelopmental and psychiatric conditions, including autism spectrum disorders and schizophrenia risk, though causality and penetrance vary and likely involve complex genetic contexts. In animal models, SAP102 deficiency reduces NMDA receptor clustering, compromises synaptic plasticity such as long-term potentiation, and impairs learning and memory tasks, supporting a role in cognitive function.