Synaptic effects of interleukin-6 on human iPSC-derived dopaminergic neurons

Increased inflammation has been linked to behavioral pathogenesis in depression. Previous studies have shown that administration of inflammatory stimuli induces motivational deficits associated with reduced activation of the ventral striatum in association with reduced dopamine (DA) availability and release. However, the underlying mechanisms of inflammation-induced DA dysfunction remain largely unknown. Here, we investigated the in vitro effects of the inflammatory cytokine interleukin (IL)-6 on female and male human induced pluripotent stem cell (iPSC)-derived DAergic neurons from healthy volunteers. We identified inhibitory effects of IL-6 on female DA neurons, including reduced DA release, neuronal firing, velocity of synaptic vesicle (SV) transport, and density of docked SV, which was further supported by transcriptomic analyses. In contrast, male DA neurons exhibited an IL-6-induced compensatory phenotype, including increased velocity and density of SV and increased presynaptic terminal density. The long noncoding RNA (lncRNA) MIAT mediated these differences in male DA neurons, potentially via interaction with genes involved in the IL-6 signaling pathway and DA regulation. Moreover, by knocking out MIAT expression in male DA neurons, IL-6-induced deficits emerged, including reduced DA release, neuronal firing, and SV docking. Lastly, we found that the Janus kinase (JAK) inhibitor baricitinib reversed the inhibitory effects of IL-6 on female DA neurons. This work extends our understanding of the impact of inflammation on DA neurons, while identifying important sex differences and pharmacologic targets, ultimately laying the foundation for anti-inflammatory treatments of depressed patients with increased inflammation.