Early life stress and serotonin transporter gene variation interact to affect the transcription of the glucocorticoid and mineralocorticoid receptors, and the co-chaperone FKBP5, in the adult rat brain

Rick H.A. van der Doelen, Francesca Calabrese, Gianluigi Guidotti, Bram Geenen, Marco A. Riva, Tamás Kozicz, Judith R. Homberg

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

The short allelic variant of the serotonin transporter (5-HTT) promoter-linked polymorphic region (5-HTTLPR) has been associated with the etiology of major depression by interaction with early life stress (ELS). A frequently observed endophenotype in depression is the abnormal regulation of levels of stress hormones such as glucocorticoids. It is hypothesized that altered central glucocorticoid influence on stress-related behavior and memory processes could underlie the depressogenic interaction of 5-HTTLPR and ELS. One possible mechanism could be the altered expression of the genes encoding the glucocorticoid and mineralocorticoid receptors (GR, MR) and their inhibitory regulator FK506-binding protein 51 (FKBP5) in stress-related forebrain areas. To test this notion, we exposed heterozygous (5-HTT+/−) and homozygous (5-HTT−/−) serotonin transporter knockout rats and their wildtype littermates (5-HTT+/+) to daily 3 h maternal separations from postnatal day 2 to 14. In the medial prefrontal cortex (mPFC) and hippocampus of the adult male offspring, we found that GR, MR, and FKBP5 mRNA levels were affected by ELS × 5-HTT genotype interaction. Specifically, 5-HTT+/+ rats exposed to ELS showed decreased GR and FKBP5 mRNA in the dorsal and ventral mPFC, respectively. In contrast, 5-HTT+/− rats showed increased MR mRNA levels in the hippocampus and 5-HTT−/− rats showed increased FKBP5 mRNA in the ventral mPFC after ELS exposure. These findings indicate that 5-HTT genotype determines the specific adaptation of GR, MR, and FKBP5 expression in response to early life adversity. Therefore, altered extra-hypothalamic glucocorticoid signaling should be considered to play a role in the depressogenic interaction of ELS and 5-HTTLPR.

Original languageEnglish (US)
Article number355
Pages (from-to)1-11
Number of pages11
JournalFrontiers in Behavioral Neuroscience
Volume8
Issue numberOCT
DOIs
StatePublished - Oct 13 2014

Keywords

  • Depression
  • Early life stress
  • FKBP5
  • Glucocorticoid receptor
  • Hippocampus
  • Medial prefrontal cortex
  • Mineralocorticoid receptor
  • Serotonin transporter

ASJC Scopus subject areas

  • Neuropsychology and Physiological Psychology
  • Cognitive Neuroscience
  • Behavioral Neuroscience

Fingerprint Dive into the research topics of 'Early life stress and serotonin transporter gene variation interact to affect the transcription of the glucocorticoid and mineralocorticoid receptors, and the co-chaperone FKBP5, in the adult rat brain'. Together they form a unique fingerprint.

  • Cite this