GEO series

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

GSE289420 Homo sapiens; Mus musculus Expression profiling by high throughput sequencing 416 samples Submitted 2026/07/28 Platform GPL24247Platform GPL24676

Summary

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.

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Direct links to NCBI, no account and no request form: the whole study as GSE289420_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 416 samples. Raw sequencing reads are also available from ENA.

Whole study · RAW.tar ↓ Series matrix ↓ All supplementary files ↗ Raw reads on ENA ↗

Also filed as BioProject PRJNA1222887 and SRA study SRP563483. Searching any of these in the dataset finder brings you back here.

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Study design

40 conditions, each sampled once — no replicated groups

Read from the first 40 of 416 sample titles: 40 distinct titles with little repetition. Check it against the sample list below before relying on it.

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