Abstract
<jats:p>Human neurons develop more slowly than non-human primate neurons. This phenomenon, termed neoteny, is thought to contribute to several human-specific features of the brain, including humans' expanded cortices. However, much of the research on this difference in neuronal development rate has focused on neuron-intrinsic drivers of developmental timing. Because astrocytes serve as critical support cells of neurons and are increasingly implicated in neuronal maturation during development, we hoped to further elucidate any species-specific divergence in function and the astrocytes' role in influencing species-specific development rate. In this study, we began with a transcriptomic characterization of human and non-human primate astrocytes in vitro. We then measured how the metabolic role of astrocytes differs between humans and non-human primates. We then performed a multi-electrode array assay and observed an increase in electrophysiological maturation in human neurons cultured with rhesus macaque astrocyte conditioned media as opposed to human astrocyte conditioned media and a change in the trajectory of neuronal development, as measured by transcriptomics. Curiously, we observed an increase in synaptogenic and axon growth-related proteins in the secretome of human astrocytes, suggesting that human astrocytes play a different, more synaptogenic and dendritic arborization-focused role in neurodevelopment than non-human primate astrocytes. Finally, we demonstrated that these changes in neuronal differentiation are in part mediated by the different metabolic roles that astrocytes play in humans versus non-human primates through chemical inhibition of a key metabolic pathway. Our results collectively suggest a cell-extrinsic role for astrocyte metabolism in shaping the differences in neurodevelopment rate and trajectory in humans versus non-human primates.</jats:p>