Abstract
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 young adulthood, 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 two to 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 the 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
A.R.K. is a co-founder, consultant and director of Neurona Therapeutics. The remaining authors declare no competing interests.
Footnotes
Here are the key revisions we made: 1. We generated an additional proteomic dataset of the postsynaptic density (PSD) from the human primary visual cortex (V1), demonstrating the generalizability of most conclusions from the prefrontal cortex (PFC). 2. We further integrated our proteomic data with single-cell RNA-sequencing data from the developing human neocortex. This integration offered more comprehensive insights into the cell type-specific developmental dynamics of PSD modules. 3. We conducted a more in-depth analysis in human and mouse cortical neurons by manipulating Rho GTPase regulators, providing additional evidence to support the critical role of Rho GTPase activation in promoting synaptic neoteny in humans.