Post-translational control of synaptic adhesion molecules: molecular mechanisms and disease implications

Synaptic cell adhesion molecules (SAMs) are crucial for organizing synapse formation, maturation, and plasticity. No longer considered static structural links between pre- and postsynaptic membranes, SAMs are now understood to be dynamic signaling platforms whose functions are precisely controlled by various post-translational modifications (PTMs). For instance, conventional N- and O-linked glycosylation regulates protein folding and surface trafficking, whereas proteoglycan modification by heparan sulfate (HS) contributes to extracellular recognition and trans-synaptic interactions. Meanwhile, phosphorylation and dephosphorylation influence scaffold recruitment, synapse type specificity, and activity-dependent signaling. Additionally, proteolytic processing and ubiquitination manage the turnover, endocytosis, and signaling duration of adhesion complexes, allowing for rapid changes in synaptic connectivity. This review synthesizes recent progress on how these PTMs regulate SAMs and neurotrophin receptors across different scales, from individual synapses to entire neural circuits. We also discuss how PTM dysregulation contributes to neurodevelopmental and neuropsychiatric disorders and highlight the possibility that interactions among distinct PTMs may form a combinatorial regulatory code that further diversifies synaptic adhesion signaling, although this concept requires further investigation.