MODELING MAJOR DEPRESSIVE DISORDER IN A DISH: INSIGHTS INTO THE MOLECULAR PATHOMECHANISMS OF MDD

Major Depressive Disorder (MDD) is a leading cause of disability globally; nevertheless, its molecular underpinnings remain elusive, and treatment responses are often inadequate. Mitochondrial dysfunction is a critical risk factor, given its role in energy production, synaptic transmission, and neurogenesis. Prior work in skin fibroblasts from MDD patients demonstrated significantly reduced basal and maximal oxygen consumption rates (OCR). In iPSC-derived neuronal progenitor cells (NPCs) from MDD patients, these bioenergetic perturbations persist. In this study, we established an in vitro model using human-iPSC-derived NPCs and neurons of MDD patients and matched healthy controls. To model physiological stress, cells were exposed to cortisol acutely (30-minutes), subacutely (24-hours), and chronically (7-days). Mitochondrial respiration and calcium (Ca²⁺) dynamics were measured. Our data show that acute cortisol exposure induces an immediate decrease in basal OCR in NPCs from both cohorts, suggesting non-genomic mitochondrial regulation. After 24-hours, both groups maintained similar suppression of basal respiration, whereas chronic exposure led to an enhancement of bioenergetic responses, weaker in MDD patients. Calcium imaging revealed that cytosolic Ca²⁺ transiently increases following 24-hours cortisol treatment, and declines again by 7-days, while mitochondrial Ca²⁺ responses vary without consistent trends across subjects. Electrophysiological analyses are currently underway to characterize ion-channel function and membrane excitability in iPSC‐neurons. Furthermore, multielectrode array (MEA) recordings are planned to investigate network‐level activity. Finally, pharmacological assays will test classical antidepressants and neurosteroids to assess their capacity to restore basal conditions. This study aims to uncover molecular mechanisms of MDD and guide the development of interventions.