Extension of cortical synaptic development distinguishes humans from chimpanzees and macaques

Over the course of ontogenesis, the human brain and human cognitive abilities develop in parallel, resulting in a phenotype strikingly distinct from that of other primates. Here, we used microarrays and RNA-sequencing to examine human-specific gene expression changes taking place during postnatal brain development in the prefrontal cortex and cerebellum of humans, chimpanzees, and rhesus macaques. We show that the most prominent human-specific expression change affects genes associated with synaptic functions and represents an extreme shift in the timing of synaptic development in the prefrontal cortex, but not the cerebellum. Consequently, peak expression of synaptic genes in the prefrontal cortex is shifted from <1 yr in chimpanzees and macaques to 5 yr in humans. This result was supported by protein expression profiles of synaptic density markers and by direct observation of synaptic density by electron microscopy. Mechanistically, the human-specific change in timing of synaptic development involves the MEF2A-mediated activity-dependent regulatory pathway. Evolutionarily, this change may have taken place after the split of the human and the Neanderthal lineages.