Identifying Molecular Substrates in a Mouse Model of the Serotonin Transporter × Environment Risk Factor for Anxiety and Depression

Valeria Carola, Giovanni Frazzetto, Tiziana Pascucci, Enrica Audero, Stefano Puglisi-Allegra, Simona Cabib, Klaus Peter Lesch, Cornelius Gross

Research output: Contribution to journalArticlepeer-review

Abstract

Background: A polymorphism in the serotonin transporter (5-HTT) gene modulates the association between adverse early experiences and risk for major depression in adulthood. Although human imaging studies have begun to elucidate the neural circuits involved in the 5-HTT × environment risk factor, a molecular understanding of this phenomenon is lacking. Such an understanding might help to identify novel targets for the diagnosis and therapy of mood disorders. To address this need, we developed a gene-environment screening paradigm in the mouse. Methods: We established a mouse model in which a heterozygous null mutation in 5-HTT moderates the effects of poor maternal care on adult anxiety and depression-related behavior. Biochemical analysis of brains from these animals was performed to identify molecular substrates of the gene, environment, and gene × environment effects. Results: Mice experiencing low maternal care showed deficient γ-aminobutyric acid-A receptor binding in the amygdala and 5-HTT heterozygous null mice showed decreased serotonin turnover in hippocampus and striatum. Strikingly, levels of brain-derived neurotrophic factor (BDNF) messenger RNA in hippocampus were elevated exclusively in 5-HTT heterozygous null mice experiencing poor maternal care, suggesting that developmental programming of hippocampal circuits might underlie the 5-HTT × environment risk factor. Conclusions: These findings demonstrate that serotonin plays a similar role in modifying the long-term behavioral effects of rearing environment in diverse mammalian species and identifies BDNF as a molecular substrate of this risk factor.

Original languageEnglish
Pages (from-to)840-846
Number of pages7
JournalBiological Psychiatry
Volume63
Issue number9
DOIs
Publication statusPublished - May 1 2008

Keywords

  • 5-HTT
  • anxiety
  • depression
  • gene × environment
  • maternal behavior

ASJC Scopus subject areas

  • Biological Psychiatry

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