Evolutionary diversification of lipid logistics shapes synaptic maturation in primates

Abstract

The prolonged developmental trajectory of the human brain (neoteny) is a defining feature of human evolution. Yet, the cellular mechanisms underlying this delay remain poorly understood. Here, comparing human and chimpanzee induced neurons and cerebral organoids, we we show that human neurons form fewer excitatory synapses and synchronize network activity later. Electron microscopy further revealed reduced synaptic vesicle docking and clustering near release sites, identifying altered presynaptic assembly as a prominent feature of human neuronal development. Unexpectedly, human neurons accumulate more, not less, membrane lipids, revealing a dissociation between lipid abundance and synaptic maturation. Transcriptomics and synaptosome proteomics resolve this paradox: chimpanzee neurons preferentially engage lipid metabolism and synaptic-maturation programs, whereas human neurons upregulate intracellular lipid transport and trafficking pathways. Together, our findings identify membrane organization as a previously unrecognized regulatory layer that controls neuronal neoteny. These results also suggest that evolutionary divergence can arise through changes in the spatial deployment of membrane lipids rather than their abundance, providing a molecular framework for understanding the evolution of human brain neoteny.