Astrocytic glutamate regulation is implicated in the development of stress-related psychiatric disorders

Severe psychological stress is one of the most potent risk factors for developing a mood or psychotic disorder, yet the underlying molecular mechanisms are poorly understood. Astrocytes are a key brain cell type associated with stress and psychiatric phenotypes in animals, but how this translates to humans is largely unknown. Here, we show that cortical astrocytes are persistently changed both physically and molecularly in humans with psychiatric disorders exposed to profound stress before diagnosis. By profiling the diversity of human astrocytes with single nucleus and spatial transcriptomics, we identified distinct alterations to glutamate-related synaptic functions, supported by histological quantification of >20,000 astrocytes. Alterations were pronounced in females compared to males and in cases exposed to profound stress during childhood. The use of human pluripotent stem cell-derived astrocytes confirmed that glutamate signalling is directly impacted by glucocorticoid activation. Our findings suggest that astrocytes are strategic pharmacological targets for future intervention strategies.