Astrocytic-supplied Cholesterol Drives Synaptic Gene Expression Programs in Developing Neurons and Downstream Astrocytic Transcriptional Programs

Overview

Journal bioRxiv

Date 2025 Feb 20

PMID 39975161

Authors

Emilia Vartiainen

Dhara Liyanage

Illinca Mazureac

Rachel A Battaglia

Matthew Tegtmeyer

Jax Xu He

He Jax Xu

Noora Rasanen

Julia Sealock

Steven McCarroll

Ralda Nehme

Olli Pietilainen

Affiliations

Soon will be listed here.

Abstract

Astrocytes participate in neuronal synaptic programs that are enriched for genetic associations in schizophrenia and autism spectrum disorders (ASD). To better 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 at 16 time points spanning 0.5 hours to 8 days. We found that upregulation in astrocytes of genes involved in cholesterol biosynthesis preceded the activation of synaptic gene programs in neurons and upregulation of the astrocytic . Neuronal knockdown of key cholesterol receptors led to downregulation of neuronal synaptic genes and induced a robust transcriptional response in the astrocytes, including further upregulation of . This suggests that astrocyte-supplied cholesterol drives these neuronal changes and that bi-directional signalling is occuring. The genes upregulated in neurons were enriched for deleterious variants in schizophrenia and neurodevelopmental disorders, suggesting that their pathogenic effect may be, in part, mediated by reduced buffering capacity for changes in the astrocyte cholesterol supply to neurons. 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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