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

Mol Psychiatry. 2014 Jun;19(6):733-41. doi: 10.1038/mp.2013.89. Epub 2013 Jul 23.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety Disorders / pathology*
  • Anxiety Disorders / physiopathology*
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Behavior, Animal / physiology
  • Brain / growth & development
  • Brain / pathology*
  • Brain / physiopathology*
  • Corticosterone / blood
  • Cytochrome P-450 CYP2C19 / genetics
  • Cytochrome P-450 CYP2C19 / metabolism*
  • Female
  • Hippocampus / growth & development
  • Hippocampus / pathology
  • Hippocampus / physiopathology
  • Humans
  • Interneurons / physiology
  • Liver / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neurons / pathology
  • Neurons / physiology
  • Organ Size
  • Proto-Oncogene Proteins c-fos / metabolism
  • RNA, Messenger / metabolism
  • Stress, Psychological / physiopathology

Substances

  • Proto-Oncogene Proteins c-fos
  • RNA, Messenger
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C18 protein, human
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP2C19
  • Corticosterone