A cross-species proteomic map reveals neoteny of human synapse development

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 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.

The proteomic landscape of synaptic diversity across brain regions and cell types

“…Imaging techniques provide the spatial resolution required to distinguish individual synapses and have illustrated substantial synaptic diversity for selected proteins (Zhu et al 2018; Cizeron et al 2020; S.-M. Guo et al 2019; Upmanyu et al 2022), but their limited multiplexing capabilities preclude the study of synaptic proteomes. The traditional biochemical isolation of synaptic terminals or synaptic elements (Takamori et al 2006; Bayés et al 2011; Roy et al 2018; Wang et al 2022; Wilhelm et al 2014) yields synapse-enriched fractions that can be analyzed by mass spectrometry-based proteomics. These preparations, however, are often of low purity and contain a heterogenous mixture of many synapse types along with non-synaptic contaminants.…”