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,Tamã¡S Kozicz,Marco A Riva,Bram Geenen,Judith R Homberg

doi:10.3389/fnbeh.2014.00355

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.

Highlights

Vulnerability to stress-related psychiatric disease is determined by a complex interplay of genome and environment
In the medial prefrontal cortex and hippocampus of the adult male offspring, we found that Glucocorticoid receptor (GR), MR, and FK506-binding protein 51 (FKBP5) mRNA levels were affected by early life stress (ELS) × 5-HTT genotype interaction
GR mRNA levels were found to be significantly affected by the interaction of ELS and 5-HTT genotype in the dorsal medial prefrontal cortex (mPFC) [F(2, 31) = 7.08, p < 0.01] and dorsal hippocampus [F(2, 33) = 4.57, p < 0.05]

Summary

Introduction

Vulnerability to stress-related psychiatric disease is determined by a complex interplay of genome and environment. The moderation of the effects of stressful life events by the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) is a well-known example of such a gene × environment (G×E) interaction (Caspi et al, 2003). The 5-HTT+/− rodents are considered to be the superior genotype model of the S-allele, as they display a two-fold reduction in 5-HTT availability (Bengel et al, 1998; Homberg et al, 2007), and increased sensitivity to stressful events (Carola et al, 2008; Narayanan et al, 2011; van der Doelen et al, 2013), just as 5-HTTLPR S-allele carriers. It has been argued that both 5-HTT+/− and 5-HTT−/− rodents are useful to study the underlying biology of ELS × 5-HTTLPR interaction (Caspi et al, 2010; Kalueff et al, 2010; Homberg and van den Hove, 2012)

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