Structural Plasticity Induced by Ketamine in Human DopaminergicNeurons as Mechanism Relevant for Treatment-Resistant Depression

摘要

The mechanisms underlying the antidepressant effects of ketamine intreatment-resistant depression are only partially understood. Reactivation ofneural plasticity in prefrontal cortex has been considered critical in mediatingthe effects of standard antidepressants, but in treatment-resistant depressionpatients with severe anhedonia, other components of the affected brain circuits,for example, the dopamine system, could be involved. In a recent article in , we showed that ketamine inducesneural plasticity in human and mouse dopaminergic neurons. Human dopaminergicneurons were differentiated from inducible pluripotent stem cells for over 60days. Mimicking the pharmacokinetic exposures occurring in treatment-resistantdepression subjects, cultures were incubated with either ketamine at 0.1 and1 µM for 1 h or with its active metabolite (2R,6R)-hydroxynorketamine at 0.1 and0.5 µM for up to 6 h. Three days after dosing, we observed aconcentration-dependent increase in dendritic arborization and soma size. Theseeffects were mediated by the activation ofα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor that triggered thepathways of mammalian target of rapamycin and extracellular signal-regulatedkinase via the engagement of brain-derived neurotrophic factor signaling, aspreviously described in rodent prefrontal cortex. Interestingly, we found thatneural plasticity induced by ketamine requires functionally intact dopamine D3receptors. These data are in keeping with our recent observation that plasticitycan be induced in human dopaminergic neurons by the D3 receptor-preferentialagonist pramipexole, whose effect as augmentation treatment intreatment-resistant depression has been reported. Overall, the evidence ofpharmacologic response in human inducible pluripotent stem cell-derived neuronscould provide complementary information to those provided by circuit-basedimaging when assessing the potential response to a given augmentationtreatment.