603. CONVERGING HUMAN-SPECIFIC EVIDENCE IMPLICATES ASTROCYTIC GLUTAMATE REGULATION IN STRESS-RELATED PSYCHIATRIC DISORDERS

Abstract Background Severe stress is the leading environmental risk factor for psychiatric disorders. Yet, we have a limited understanding of what underlies this association in humans. Astrocytes, an abundant non-neuronal cell type, are key regulators of synaptic transmission. Rodent studies indicate that stress impairs the capacity to regulate neurotransmission, which can drive the development of psychiatric-like symptoms. However, psychopathology in humans is complex, and these cells are poorly evolutionarily conserved, necessitating human-relevant evidence to translate these findings. Aims & Objectives To understand the profile of human prefrontal cortex astrocytes and how they are altered by stress exposure in the context of neuropsychiatric disorders. Method We used single nucleus RNA-sequencing (n=87) and spatial transcriptomics (n=13) from the orbitofrontal cortex (BA11) to examine human astrocyte diversity. We used this basis of diversity to examine how individuals diagnosed with a psychiatric disorder stratified by profound stress exposure prior to diagnosis differ from those without. Immunohistochemistry (IHC) of was used to further dissect the impact of stress on the morphology of >20,000 astrocytes. The functional impacts of stress were examined using astrocytes (iAsts) differentiated from human embryonic stem cells. iAsts were treated with 100nM dexamethasone (DEX) for 1-7 days to activate the cortisol response. Neurotransmitter clearance and neurotransmitter Ca2+ response were quantified. Results We identified that grey matter astrocytes involved in synapse homeostasis were delineable between stress-stratified cases. Exploratory analysis identified that effects were associated with sex (greater in females) and timing of stress (greater in early-life exposure). EAAT2-expressing astrocytes were denser across the layers of the cortex (P=0.002-0.016) and covered a greater domain, particularly in layers V-VI (Padj=2.43x10-4). iAsts treated with DEX had reduced glutamate clearance after 3 days (P=3.5x10-6) and increased Ca2+ response to both glutamate (P=0.004) and NMDA (P=0.0047) after 7 days. Discussion & Conclusions Our findings indicate that astrocytes are associated with lasting changes in individuals with psychiatric disorders exposed to profound stress, especially in grey matter astrocytes involved in glutamate regulation. These cells may be key responders to stress and, thus, an important focus for intervention or prevention strategies. This presentation provides novel data on the lasting impacts of severe psychological stress on astrocytes in the human orbitofrontal cortex and the first functional profile of human-derived astrocytes in response to a stress paradigm. Dr Matosin will present unique and previously unpublished data showing the classification of human astrocytes and their diversity in the human cortex, and the significant effects of stress exposure in people who lived with psychiatric disorders. Dr Matosin will also discuss the role of sex and stress timing in these findings and the connections between glucocorticoid and glutamate signalling with relevance to psychopathology.

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