Astrocyte metabolic programs diverge across primate evolution and are linked to species-specific neuronal development

Humans are characterized by changes in neuronal development compared to non-human primates (NHPs), and metabolic changes are implicated in these species' differences. However, most research has focused on changes in the neurons and neural progenitor cells themselves, but astrocytes are crucial metabolic cells in the brain. Here, we identified a delayed onset of gliogenesis in human versus NHP organoid models. iPSC-derived astrocytes also revealed distinct metabolic profiles: NHP astrocytes exhibit increased serine and glycine synthesis, whereas human astrocytes show elevated lactate secretion, suggesting metabolic reprogramming of astrocytes across primate evolution. Astrocyte secretomes also differed, with human astrocyte secretomes enriched for axon-growth proteins. We then assessed the impact of these different species' astrocyte secretomes on neuronal development. Conditioned media from NHPs as compared to humans led to increased electrophysiological activity and altered transcriptomic signatures of neuronal development in human neurons. Chemical PHGDH inhibition is consistent with a partial contribution of astrocytic serine/glycine metabolism to these species-specific effects. Together, these findings reveal a metabolic and secretory divergence between human and NHP astrocytes linked to species-specific neuronal development.