Modeling Suicidal Major Depression Disorder in iPSC-derived GABAergic neurons reveals altered expression of 5HT2C

Suicidal major depression (sMDD) poses a substantial burden to both personal and public health. Dysfunction of GABA interneurons has been observed in studies on postmortem tissue from patients with sMDD. However, there is no effective research model for studying the etiology of sMDD. In the current study, we generated three induced pluripotent stem cell (iPSC) lines from three MDD patients who had committed suicide, and differentiated GABA interneurons (GINs) from both patient and control (CTRL) iPSCs. sMDD GINs exhibited altered differentiation ratios of calbindin (CB) and calretinin (CR), abnormal neuronal morphology and electrophysiological activities, as well as decreased calcium signaling, in contrast to CTRL GINs. Using single-cell sequences and bulk cell sequences, we found that the expression of the serotoninergic receptor 2C subtype (5-HT2C) was decreased in sMDD GINs. Furthermore, three FDA-approved small molecules were tested against 5-HT2C, and trazodone hydrochloride (Trzd) could restore the defects in sMDD GINs. Our findings provide a human model for studying the molecular mechanisms and drug targets for sMDD.