Dysregulation of glutamatergic and GABAergic neurons in Treatment-Resistant Depression: Insights from patient-derived neurons

Major depressive disorder (MDD) is a common condition and a leading cause of global health burden. Despite the availability of pharmacological treatments, many patients do not respond to at least two antidepressant therapies, leading to treatment-resistant depression (TRD). The underlying molecular mechanisms of TRD remain unclear, partly due to the limitations of current preclinical models. Induced pluripotent stem cells (iPSCs) represent a novel approach to study MDD and TRD, allowing for examining patient-derived neurons at both molecular and cellular levels. Previous studies using iPSCs from MDD and TRD patients have focused on single-cell populations. We now propose to employ the iPSCs technology to derive multiple neuronal subtypes, including GABAergic and glutamatergic neurons, as an in vitro model for replicating the neurobiological complexity of MDD. iPSCs-derived neurons from two female TRD patients and a healthy control were used. We found that the two TRD cultures showed patient-specific abnormalities in the number and/or morphology of neuronal subpopulations, but converged on an excitatory/inhibitory imbalance, which is hypothesized to underlie MDD and TRD. Neuron morphology was analyzed after fluoxetine treatment, showing that TRD neurons were resistant to the morphological changes observed in control neurons, consistent with fluoxetine failing to relieve depressive symptoms in these patients. Thus, this multi-cell-type iPSC model may offer a platform for exploring cellular mechanisms in TRD patients and could help in developing personalized treatment strategies.