Depressive patient‐derived GABA interneurons reveal abnormal neural activity associated with HTR2C

Autor: Kaiqin Lu, Yuan Hong, Mengdan Tao, Luping Shen, Zhilong Zheng, Kaiheng Fang, Fang Yuan, Min Xu, Chun Wang, Dongya Zhu, Xing Guo, Yan Liu
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: EMBO Molecular Medicine, Vol 15, Iss 1, Pp n/a-n/a (2023)
Druh dokumentu: article
ISSN: 1757-4684
1757-4676
DOI: 10.15252/emmm.202216364
Popis: Abstract Major depressive disorder with suicide behavior (sMDD) is a severe 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.
Databáze: Directory of Open Access Journals
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