hiPSC-derived astrocytes from individuals with schizophrenia promote alterations in phagocytosis and chemotaxis of microglial-like cells

Neuroinflammation, particularly astrocyte reactivity, are increasingly linked to schizophrenia (SCZ). Yet, the crosstalk between astrocytes and microglia in SCZ, especially under pro-inflammatory conditions, remains unclear. Here, we apply human induced pluripotent stem cells (hiPSCs) to compare the reactivity of astrocytes from individuals with SCZ and neurotypical controls, towards resolving how patient-derived astrocytes affect microglial biology. TNF-ɑ stimulation of SCZ astrocytes, relative to control astrocytes, trigger an increase in expression of pro-inflammatory cytokines and CX3CL1, a chemokine involved in chemotaxis and synapse pruning. Transcriptomic analyses reveal that TNF-ɑ-stimulated SCZ astrocytes promote the downregulation of biological processes associated with phagocytosis and chemotaxis in induced microglial-like cells (iMGs). Interestingly, TNF-ɑ-stimulated SCZ astrocytes lead to reduced synaptoneurosomes engulfment by iMGs. Alternatively, TNF-ɑ-stimulated astrocytes (control and SCZ) induce microglial migration in a CX3CR1-dependent manner. Surprisingly, TNF-ɑ-stimulated SCZ astrocytes do not promote a more pronounced microglial chemotaxis, despite secreting twice as much CX3CL1 compared to stimulated control astrocytes, possibly due to lower CX3CR1 plasma membrane content after exposure to A _CM from individuals with SCZ. Altogether, these findings suggest that astrocytes contribute to SCZ pathology by altering normal microglial function.