Publication Date
10-1-2023
Journal
Nature
DOI
10.1038/s41586-023-06542-2
PMID
37704727
PMCID
PMC10576238
PubMedCentral® Posted Date
1-1-2024
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Adolescent, Animals, Child, Child, Preschool, Humans, Infant, Infant, Newborn, Mice, Young Adult, Cognition, Dendritic Spines, Gestational Age, Macaca, Neurons, Post-Synaptic Density, Proteomics, Rho Guanine Nucleotide Exchange Factors, Signal Transduction, Species Specificity, Synapses
Abstract
The molecular mechanisms and evolutionary changes accompanying synapse development are still poorly understood1,2. Here we generate a cross-species proteomic map of synapse development in the human, macaque and mouse neocortex. By tracking the changes of more than 1,000 postsynaptic density (PSD) proteins from midgestation to young adulthood, we find that PSD maturation in humans separates into three major phases that are dominated by distinct pathways. Cross-species comparisons reveal that human PSDs mature about two to three times slower than those of other species and contain higher levels of Rho guanine nucleotide exchange factors (RhoGEFs) in the perinatal period. Enhancement of RhoGEF signalling in human neurons delays 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. Our proteomic map of synapse development provides a blueprint for studying the molecular basis and evolutionary changes of synapse maturation.
Included in
Diseases Commons, Neurology Commons, Neurosciences Commons, Pediatrics Commons
