Decreased hippocampal volume and increased anxiety in a transgenic mouse model expressing the human CYP2C19 gene

Abstract

Selective serotonin reuptake inhibitors, tricyclic antidepressants, various psychoactive drugs, as well as endogenous steroids and cannabinoid-like compounds are metabolized by the polymorphic cytochrome P450 2C19 (CYP2C19). Absence of this enzyme has been recently shown to associate with lower levels of depressive symptoms in human subjects. To investigate endogenous functions of CYP2C19 and its potential role in brain function, we have used a transgenic mouse model carrying the human CYP2C19 gene. Here, CYP2C19 was expressed in the developing fetal, but not adult brain and was associated with altered fetal brain morphology, where mice homozygous for the CYP2C19 transgenic insert had severely underdeveloped hippocampus and complete callosal agenesis and high neonatal lethality. CYP2C19 expression was also found in human fetal brain. In adult hemizygous mice we observed besides decreased hippocampal volume, an altered neuronal composition in the hippocampal dentate gyrus. Reduced hippocampal volumes have been reported in several psychiatric disorders, supporting the relevance of this model. Here we found that adult hemizygous CYP2C19 transgenic mice demonstrate behavior indicative of increased stress and anxiety based on four different tests. We hypothesize that expression of the CYP2C19 enzyme prenatally may affect brain development by metabolizing endogenous compounds influencing this development. Furthermore, CYP2C19 polymorphism may have a role in interindividual susceptibility for psychiatric disorders.

Direct inhibition of retinoic acid catabolism by fluoxetine

“…Most interestingly in this context is a study recently published by Persson and colleagues (Persson et al 2014), demonstrating hippocampal atrophy and depressive-like symptoms in a mouse model expressing the human CYP2C19 gene. Although a precise mechanism is not revealed, the authors indeed suggest (yet to be identified) ''endogenous substrates'' of overexpressed CYP2C19 to mediate the observed effects (Persson et al 2014). Most interestingly, however, CYP2C19 is also an isozyme involved in the metabolism of endogenous RA (McSorley and Daly 2000).…”

“…Interestingly, functionally relevant polymorphisms of RA-degrading CYP450 isozymes have recently been linked with major depression and response to antidepressant treatment (Sim et al 2010;Ruano et al 2011). Most interestingly in this context is a study recently published by Persson and colleagues (Persson et al 2014), demonstrating hippocampal atrophy and depressive-like symptoms in a mouse model expressing the human CYP2C19 gene. Although a precise mechanism is not revealed, the authors indeed suggest (yet to be identified) ''endogenous substrates'' of overexpressed CYP2C19 to mediate the observed effects (Persson et al 2014).…”

Enhancement of Local Retionic Acid Signaling: A Pivotal Mechanism in Fluoxetine's Pleiotropic Actions

“…Highlighting the clinical impact of the CYP450-system in the context of MDD, an association has been found between functionally relevant polymorphisms of RA-catabolizing CYP450-isozymes, such as CYP2C19, on the one hand, and response to antidepressant treatment 26 as well as prevalence of depressive symptoms and risk for depression and suicide itself on the other hand 27,28 . Consequently, transgenic mice expressing the mutant human CYP2C19 gene were found to exhibit hippocampal atrophy and depressive-like symptoms 29 . Against the background of RA´s involvement in MDD pathogenesis and its catabolism via CYP450-isozymes, RA signaling might represent a missing link between pathologically increased catabolism (e.g.…”

A combined high CYP2D6-CYP2C19 metabolic capacity is associated with the severity of suicide attempt as measured by objective circumstances

“…CYP2C19 expression has been recently shown in the human fetal brain. 21 It also participates in the metabolism of endogenous steroids and cannabinoid-like compounds, 20 which might collectively underlie the observed alterations in brain development and affective behavior observed in a transgenic mouse model carrying the human CYP2C19. 21 Consistently, individuals who do not produce active CYP2C19 protein because they are homozygous for the null protein activity allele *2 selfreported lower levels of depressive symptoms.…”

“…21 It also participates in the metabolism of endogenous steroids and cannabinoid-like compounds, 20 which might collectively underlie the observed alterations in brain development and affective behavior observed in a transgenic mouse model carrying the human CYP2C19. 21 Consistently, individuals who do not produce active CYP2C19 protein because they are homozygous for the null protein activity allele *2 selfreported lower levels of depressive symptoms. 22 In order to evaluate the combined influence of these two highly polymorphic genes involved in the metabolism of CNS drugs and substances, a helpful strategy might be based on calculating a 'drug metabolic capacity score', which we propose.…”