title: 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.
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.
authors.affiliation: Department of Anatomy, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center Nijmegen, Netherlands ; Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center Nijmegen, Netherlands.
authors.forename: Rick H A
authors.initials: RH
authors.lastname: van der Doelen
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Calabrese
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano Milan, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Guidotti
authors.affiliation: Department of Anatomy, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center Nijmegen, Netherlands.
authors.forename: Bram
authors.initials: B
authors.lastname: Geenen
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano Milan, Italy.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Riva
authors.affiliation: Department of Anatomy, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center Nijmegen, Netherlands.
authors.forename: Tamás
authors.initials: T
authors.lastname: Kozicz
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center Nijmegen, Netherlands.
authors.forename: Judith R
authors.initials: JR
authors.lastname: Homberg
keywords: FKBP5; depression; early life stress; glucocorticoid receptor; hippocampus; medial prefrontal cortex; mineralocorticoid receptor; serotonin transporter