Cortisol-dependent impairment of dendrite plasticity in human dopaminergic neurons derived from hiPSCs is restored by ketamine: Relevance for major depressive disorders

Impaired neuroplasticity in neurons endowed in limbic circuits is considered a hallmark of chronic stress and depression. The reasons for this impairment are still partially unclear, but converging findings suggest that it can be reverted by exposure to rapid-acting antidepressants. In this study we revamped the hypothesis that the abnormal high circulating levels of cortisol observed in Major Depressive Disorders with anhedonia may contribute to drive the limbic circuit neuroplasticity impairment. Here we used an established in-vitro translational model based on human iPSC-derived dopaminergic neurons to extend the evidence obtained in rodents of glucocorticoid-induced hypotrophy of cortical dendrites. The predictive value of this model was tested by assessing the reversal potential of rapid-acting antidepressants on cortisol-induced hypotrophy. Human mesencephalic dopaminergic neurons were differentiated in-vitro from healthy donor iPSCs for 60–70 days. Cortisol effects were assessed by measuring maximal dendrite length, primary dendrite number and soma area 3 days after last exposure. Concentration- and time-response curves were initially established. Cortisol produced a concentration- and time-dependent reduction of dendritic arborization of human dopaminergic neurons, with maximal effects at 50 μM for 4-day dosing. These effects were reverted when followed by 1-hr exposure to ketamine or (2R,6R)-hydroxynorketamine at concentrations of 0.01 μM and 0.05 μM, respectively, resulting approximately 10- or 100-fold lower than those effective in neurons not exposed to cortisol. Overall, in this study high cortisol impaired dendritic arborization in human dopaminergic neurons and sensitized their neuroplasticity response to very low doses of rapid-acting antidepressants known to upregulate AMPA-mediated glutamatergic neurotransmission.