Abstract The maturation of neurons and the development of synapses – while emblematic of neurons – also rely on interactions with astrocytes and other glia. To study the role of glia-neuron interactions, we analyzed the transcriptomes of human pluripotent stem cell (hPSC)-derived neurons, from a total of 80 human donors, that were cultured with or without contact with glial cells. We found that the presence of astrocytes enhanced synaptic gene-expression programs in neurons. These changes in neuronal synaptic gene expression correlated with increased expression in the co-cultured glia of genes that encode synaptic cell adhesion molecules, and they were greatly enhanced in the glia in coculture. Both the neuronal and astrocyte gene-expression programs were enriched for genes that are linked to schizophrenia risk. Physical contact between the two cell types was required for the induction of synaptic programs in neurons. Our results suggest that astrocyte-expressed genes with synaptic functions are associated with stronger expression of synaptic genetic programs in neurons and suggest a potential role for astrocyte-neuron interactions in schizophrenia.

Astrocytic cell adhesion genes linked to schizophrenia correlate with synaptic programs in neurons