Extension of cortical synaptic development distinguishes humans from chimpanzees and macaques

Abstract

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.

Synaptogenesis and development of pyramidal neuron dendritic morphology in the chimpanzee neocortex resembles humans

“…Evidence for an extended period of synaptic refinement in chimpanzees is consistent with previous findings indicating that prefrontal white matter development is prolonged until at least the mid-juvenile period in this species (28). This finding contrasts, however, with a recent report by Liu et al (10), suggesting that relatively increased synapse-associated gene expression in the prefrontal cortex continues until 5 y of age in humans only, but in chimpanzees and macaques synaptic gene expression peaks within the first year of life. Because the analysis of Liu et al (10) included only three chimpanzee brains between 1 y of age and adulthood, however, differences in the sample sizes represented in these two studies could contribute to the divergent findings, especially because interindividual variation is pronounced.…”

“…This finding contrasts, however, with a recent report by Liu et al (10), suggesting that relatively increased synapse-associated gene expression in the prefrontal cortex continues until 5 y of age in humans only, but in chimpanzees and macaques synaptic gene expression peaks within the first year of life. Because the analysis of Liu et al (10) included only three chimpanzee brains between 1 y of age and adulthood, however, differences in the sample sizes represented in these two studies could contribute to the divergent findings, especially because interindividual variation is pronounced. Additionally, little is still known regarding how gene expression regulates anatomical changes in synapse densities during development (36).…”

“…We found no differences in the timing of peak synapse density across different regions of the chimpanzee neocortex. These findings appear to contrast with reports in humans indicating that the prefrontal cortex matures later than other cortical areas, as reflected by metabolic rate, cortical thickness, and peak synapse density (10,11,15,17,39). It should be noted, however, that prior data suggesting a relative delay of synaptogenesis in the human prefrontal cortex are based on a single study of a modest sample that lacked statistical analysis (11).…”

“…Concomitantly, the postnatal refinement of cortical microstructure in humans progresses along a more protracted schedule relative to macaques. In macaques, the process of synaptogenesis, whereby new synapses are formed, peaks during infancy at around 3 mo of age, and pruning of excess synapses is completed by the end of adolescence (9,10). In contrast, in humans, peak synapse density occurs in mid-childhood around 5 y of age (10,11), with pruning of synapses extending into the third decade of life (12).…”

“…With regard to synaptogenesis, current data from chimpanzees are extremely limited (10). Therefore, the present study examined two developmental markers in chimpanzees, synaptogenesis and dendritic growth of pyramidal neurons, in four regions, including prestriate visual (area 18), primary motor (area 4), primary somatosensory (area 3b), and prefrontal (area 10) cortices.…”