Major depressive disorder with suicide behavior (sMDD) is a server mood disorder, bringing tremendous burden to family and society. Although reduced gamma amino butyric acid (GABA) level has been observed in postmortem tissues of sMDD patients, the molecular mechanism by which GABA levels are altered remains elusive. In this study, we generated induced pluripotent stem cells (iPSC) from five sMDD patients and differentiated the iPSCs to GABAergic interneurons (GINs) and ventral forebrain organoids. sMDD GINs exhibited altered neuronal morphology and increased neural firing, as well as weakened calcium signaling propagation, compared with controls. Transcriptomic sequencing revealed that a decreased expression of serotoninergic receptor 2C (5-HT2C) may cause the defected neuronal activity in sMDD. Furthermore, targeting 5-HT2C receptor, using a small molecule agonist or genetic approach, restored neuronal activity deficits in sMDD GINs. Our findings provide a human cellular model for studying the molecular mechanisms and drug discoveries for sMDD.
Keyphrases
- induced pluripotent stem cells
- major depressive disorder
- end stage renal disease
- bipolar disorder
- small molecule
- ejection fraction
- newly diagnosed
- chronic kidney disease
- single cell
- endothelial cells
- peritoneal dialysis
- traumatic brain injury
- prognostic factors
- poor prognosis
- genome wide
- gene expression
- spinal cord
- emergency department
- dna methylation
- physical activity
- cerebral ischemia
- binding protein
- protein protein
- patient reported
- subarachnoid hemorrhage
- brain injury
- long non coding rna
- cancer therapy
- adverse drug