Lycium barbarum polysaccharide-glycoprotein ameliorates abnormal neural activity through regulating ER stress in depressive patient-derived ventral forebrain organoids

Major depressive disorder (MDD) is a severe mood disorder that imposes a significant burden on individuals, families, and society. Despite considerable advances in research, most current treatments for depression remain ineffective for many patients. Given the potential antidepressant properties of lycium barbarum glycopeptide (LbGp), there is an urgent need to establish a platform for evaluating its therapeutic efficacy and underlying mechanisms. In this study, we generated ventral forebrain organoids derived from MDD patient and observed abnormal neuronal morphology along with impaired calcium dynamics and electrical activity. Treatment with LbGp effectively restored these phenotypic alterations in MDD organoids. Transcriptomic analysis further revealed that LbGp could ameliorate endoplasmic reticulum (ER) stress in MDD organoids. Furthermore, to investigate the role of ER stress, we treated control organoids with the ER stress agonist CCT020312, which induced similar altered neural activity phenotypes that as observed in MDD organoids. Remarkably, LbGp treatment rescued the phenotypic defects in control organoids induced by CCT020312. In conclusion, this study utilized ventral forebrain organoids derived from MDD patients and demonstrated that LbGp ameliorates MDD through the modulation of ER stress.