Differential effects of lithium on metabolic dysfunctions in astrocytes derived from bipolar disorder patients

Metabolic alterations have been observed in the brains of patients with bipolar disorder (BD), a neuropsychiatric disorder characterized by alternating episodes of mania and depression. However, the specific contributions of glial cells to these metabolic changes remain largely unknown. Here, we investigate the metabolic characteristics of induced astrocytes (iAstrocytes) derived from induced pluripotent stem cells of BD patients-classified by lithium responsiveness-and healthy controls. Transcriptomic analyses revealed dysregulated expression of genes associated with metabolic diseases in BD iAstrocytes. Compared to control iAstrocytes, BD iAstrocytes showed decreased mitochondrial respiration, increased glycolysis, and elevated lactate secretion, indicating impaired mitochondrial function. These defects were further supported by downregulation of oxidative phosphorylation complex proteins and decreased reactive oxygen species levels. Notably, BD iAstrocytes showed substantial lipid droplet (LD) accumulation, potentially as a consequence of disrupted metabolic homeostasis. Lithium treatment reduced LD levels in lithium-responsive (Li-R) iAstrocytes but failed to restore mitochondrial respiration or normalize lactate secretion. In co-culture with human neurons, lithium-nonresponsive (Li-NR) iAstrocytes exhibited enhanced uptake of neuron-derived lipids and selectively increased neuronal excitability. Metabolomic profiling revealed distinct metabolite signatures between Li-R and Li-NR iAstrocytes, suggesting lithium responsiveness as a key axis of metabolic heterogeneity. Together, our findings identify astrocyte-specific metabolic dysfunction as a hallmark of BD and reveal divergent roles of Li-R and Li-NR iAstrocytes in modulating neuronal function. LD accumulation in Li-NR iAstrocytes may serve as a functional readout for drug screening to identify alternative treatments for patients unresponsive to lithium.