A cross-species proteomic map of synapse development reveals neoteny during human postsynaptic density maturation

The molecular mechanisms and evolutionary changes accompanying synapse development are still poorly understood. Here, we generated a cross-species proteomic map of synapse development in the human, macaque, and mouse neocortex. By tracking the changes of >1,000 postsynaptic density (PSD) proteins from midgestation to adolescence, we found that PSD maturation in humans separates into three major phases that are dominated by distinct pathways. Cross-species comparisons reveal that the human PSD matures about three times slower than other species and contains higher levels of Rho guanine nucleotide exchange factors (RhoGEFs) in the perinatal period. Enhancement of the RhoGEF signaling in human neurons delays the morphological maturation of dendritic spines and functional maturation of synapses, potentially contributing to the neotenic traits of human brain development. In addition, PSD proteins can be divided into four modules that exert stage- and cell type-specific functions, possibly explaining their differential associations with cognitive functions and diseases. Together, our proteomic map of synapse development provides a blueprint for studying the molecular basis and evolutionary changes of synapse maturation. ### Competing Interest Statement The authors have declared no competing interest.