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|Title:||Elevated CYP2C19 expression is associated with depressive symptoms and hippocampal homeostasis impairment|
de Quervain, D.
|Citation:||Molecular Psychiatry, 2017; 22(8):1155-1163|
|MM Jukić, N Opel, J Ström, T Carrillo-Roa, S Miksys, M Novalen, A Renblom, SC Sim, EM Peñas-Lledó, P Courtet, A Llerena, BT Baune, DJ de Quervain, A Papassotiropoulos, RF Tyndale, EB Binder, U Dannlowski and M Ingelman-Sundberg|
|Abstract:||The polymorphic CYP2C19 enzyme metabolizes psychoactive compounds and is expressed in the adult liver and fetal brain. Previously, we demonstrated that the absence of CYP2C19 is associated with lower levels of depressive symptoms in 1472 Swedes. Conversely, transgenic mice carrying the human CYP2C19 gene (2C19TG) have shown an anxious phenotype and decrease in hippocampal volume and adult neurogenesis. The aims of this study were to: (1) examine whether the 2C19TG findings could be translated to humans, (2) evaluate the usefulness of the 2C19TG strain as a tool for preclinical screening of new antidepressants and (3) provide an insight into the molecular underpinnings of the 2C19TG phenotype. In humans, we found that the absence of CYP2C19 was associated with a bilateral hippocampal volume increase in two independent healthy cohorts (N=386 and 1032) and a lower prevalence of major depressive disorder and depression severity in African-Americans (N=3848). Moreover, genetically determined high CYP2C19 enzymatic capacity was associated with higher suicidality in depressed suicide attempters (N=209). 2C19TG mice showed high stress sensitivity, impaired hippocampal Bdnf homeostasis in stress, and more despair-like behavior in the forced swim test (FST). After the treatment with citalopram and 5-HT1A receptor agonist 8OH-DPAT, the reduction in immobility time in the FST was more pronounced in 2C19TG mice compared with WTs. Conversely, in the 2C19TG hippocampus, metabolic turnover of serotonin was reduced, whereas ERK1/2 and GSK3β phosphorylation was increased. Altogether, this study indicates that elevated CYP2C19 expression is associated with depressive symptoms, reduced hippocampal volume and impairment of hippocampal serotonin and BDNF homeostasis.Molecular Psychiatry advance online publication, 29 November 2016; doi:10.1038/mp.2016.204.|
|Keywords:||Hippocampus; Animals; Mice, Transgenic; Humans; Mice; Serotonin; Citalopram; Brain-Derived Neurotrophic Factor; Receptor, Serotonin, 5-HT1A; Behavior, Animal; Depression; Anxiety; Anxiety Disorders; Depressive Disorder, Major; Homeostasis; African Americans; Neurogenesis; Serotonin 5-HT1 Receptor Agonists; Cytochrome P-450 CYP2C19|
|Description:||Published online 29 November 2016. Corrected by: Erratum: Elevated CYP2C19 expression is associated with depressive symptoms and hippocampal homeostasis impairment, in Vol. 22, Issue 8, 124. The ninth and eleventh authors’ affiliations were presented incorrectly. They should have been linked to the following affiliations: A Llerena - 7CICAB Clinical Research Center, Extremadura University Hospital and Medical School, Badajoz, Spain. 8CIBERSAM, Madrid, Spain. EM Peñas-Lledó - 7CICAB Clinical Research Center, Extremadura University Hospital and Medical School, Badajoz, Spain.|
|Rights:||© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved|
|Appears in Collections:||Psychiatry publications|
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