Neurodevelopmental Disorders Associated with PSD-95 and Its Interaction Partners

Int J Mol Sci. 2022 Apr 15;23(8):4390. doi: 10.3390/ijms23084390.


The postsynaptic density (PSD) is a massive protein complex, critical for synaptic strength and plasticity in excitatory neurons. Here, the scaffolding protein PSD-95 plays a crucial role as it organizes key PSD components essential for synaptic signaling, development, and survival. Recently, variants in DLG4 encoding PSD-95 were found to cause a neurodevelopmental disorder with a variety of clinical features including intellectual disability, developmental delay, and epilepsy. Genetic variants in several of the interaction partners of PSD-95 are associated with similar phenotypes, suggesting that deficient PSD-95 may affect the interaction partners, explaining the overlapping symptoms. Here, we review the transmembrane interaction partners of PSD-95 and their association with neurodevelopmental disorders. We assess how the structural changes induced by DLG4 missense variants may disrupt or alter such protein-protein interactions, and we argue that the pathological effect of DLG4 variants is, at least partly, exerted indirectly through interaction partners of PSD-95. This review presents a direction for functional studies to elucidate the pathogenic mechanism of deficient PSD-95, providing clues for therapeutic strategies.

Keywords: DLG4; clinical genetics; epilepsy; excitatory synapses; glutamate signaling; intellectual disability; postsynaptic density; synaptopathy.

Publication types

  • Review

MeSH terms

  • Disks Large Homolog 4 Protein / genetics
  • Disks Large Homolog 4 Protein / metabolism
  • Humans
  • Intellectual Disability* / metabolism
  • Neurodevelopmental Disorders* / genetics
  • Neurodevelopmental Disorders* / metabolism
  • Phenotype
  • Post-Synaptic Density / metabolism
  • Synapses / metabolism


  • DLG4 protein, human
  • Disks Large Homolog 4 Protein