Open AccessAltered serotonergic circuitry in SSRI-resistant major depressive disorder patient-derived neurons
Author(s) -
Krishna C. Vadodaria,
Yuan Ji,
Michelle Skime,
Apuã C.M. Paquola,
T. J. N. Nelson,
Daniel Hall-Flavin,
Kelly J. Heard,
Callie Fredlender,
Yalin Deng,
James Elkins,
Komal Dani,
Amy Le,
Maria C. Marchetto,
Richard M. Weinshilboum,
Fred H. Gage
Publication year - 2019
Publication title -
molecular psychiatry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.071
H-Index - 213
eISSN - 1476-5578
pISSN - 1359-4184
DOI - 10.1038/s41380-019-0377-5
Subject(s) - serotonergic , neuroscience , serotonin , neurite , induced pluripotent stem cell , reuptake , major depressive disorder , psychology , biology , medicine , gene , embryonic stem cell , genetics , receptor , cognition , in vitro
Disrupted serotonergic neurotransmission has long been implicated in major depressive disorder (MDD), for which selective serotonin reuptake inhibitors (SSRIs) are the first line of treatment. However, a significant percentage of patients remain SSRI-resistant and it is unclear whether and how alterations in serotonergic neurons contribute to SSRI resistance in these patients. Induced pluripotent stem cells (iPSCs) facilitate the study of patient-specific neural subtypes that are typically inaccessible in living patients, enabling the discovery of disease-related phenotypes. In our study of a well-characterized cohort of over 800 MDD patients, we generated iPSCs and serotonergic neurons from three extreme SSRI-remitters (R) and SSRI-nonremitters (NR). We studied serotonin (5-HT) biochemistry and observed no significant differences in 5-HT release and reuptake or in genes related to 5-HT biochemistry. NR patient-derived serotonergic neurons exhibited altered neurite growth and morphology downstream of lowered expression of key Protocadherin alpha genes as compared to healthy controls and Rs. Furthermore, knockdown of Protocadherin alpha genes directly regulated iPSC-derived neurite length and morphology. Our results suggest that intrinsic differences in serotonergic neuron morphology and the resulting circuitry may contribute to SSRI resistance in MDD patients.