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Astrocytic-supplied cholesterol drives synaptic gene expression programs in developing neurons and downstream
Emilia Vartiainen1, Dhara Liyanage2, Illinca Mazureac2
1Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
Biorxiv : the Preprint Server for Biology
|February 20, 2025
Summary
Astrocyte cholesterol production influences neuronal development and synaptic gene activation, crucial for neurodevelopmental disorders like schizophrenia and autism spectrum disorder (ASD). This bidirectional signaling highlights lipid metabolism
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Astrocytes are integral to neuronal synaptic function.
- Genetic links exist between astrocyte-neuron interactions and schizophrenia/autism spectrum disorder (ASD).
Purpose of the Study:
- Investigate the induction of co-regulated cellular programs during early neuronal development.
- Elucidate the role of astrocyte cholesterol biosynthesis in neuronal synaptic gene activation.
Main Methods:
- Co-culture and mono-culture of astrocytes and iPSC-derived neurons.
- Analysis across 16 time points (0.5 hours to 8 days).
- Gene expression profiling and knockdown experiments targeting neuronal cholesterol receptors.
Main Results:
- Astrocyte cholesterol biosynthesis gene upregulation preceded neuronal synaptic gene activation.
- Neuronal knockdown of cholesterol receptors decreased neuronal synaptic genes and increased astrocytic Nrxn1.
- Evidence of bidirectional signaling between astrocytes and neurons regarding cholesterol.
Conclusions:
- Astrocyte-derived cholesterol significantly impacts neuronal synaptic gene expression.
- Disruptions in astrocyte cholesterol supply may contribute to the pathophysiology of neurodevelopmental disorders.
- Astrocyte-neuron lipid metabolism and signaling are critical in psychiatric and neurodevelopmental conditions.
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