Astrocyte-derived cholesterol drives synaptic gene expression in developing neurons and reciprocal astrocytic transcriptional programs

Astrocytes participate in neuronal synaptic programs enriched for genetic associations in schizophrenia and autism spectrum disorders (ASD). To understand how these co-regulated cellular programs are induced during early neuronal development, we studied astrocytes and iPSC-derived neurons in co-cultures and mono-cultures across 16 time points spanning 0.5 hours to 8 days. We found that upregulation of astrocytic cholesterol biosynthesis genes preceded the activation of synaptic gene programs in neurons and upregulation of astrocytic Nrxn1. Neuronal knockdown of key cholesterol receptors led to downregulation of neuronal synaptic genes and induced a robust transcriptional response in astrocytes, including further upregulation of Nrxn1. This suggests that astrocyte-supplied cholesterol drives neuronal synaptic changes and that bi-directional signalling is occurring. The upregulated neuronal genes were enriched for deleterious variants associated with schizophrenia and neurodevelopmental disorders, suggesting that their pathogenic effect may be, in part, mediated by reduced neuronal buffering capacity against fluctuations in astrocyte-derived cholesterol supply. These findings highlight the critical role of astrocyte-neuron interactions in psychiatric and neurodevelopmental disorders, particularly in relation to lipid metabolism and synaptic plasticity.