TY - JOUR
T1 - 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
AU - van der Doelen, Rick H.A.
AU - Calabrese, Francesca
AU - Guidotti, Gianluigi
AU - Geenen, Bram
AU - Riva, Marco A.
AU - Kozicz, Tamás
AU - Homberg, Judith R.
N1 - Publisher Copyright:
© 2014 van der Doelen, Calabrese, Guidotti, Geenen, Riva, Kozicz and Homberg.
PY - 2014/10/13
Y1 - 2014/10/13
N2 - 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.
AB - 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.
KW - Depression
KW - Early life stress
KW - FKBP5
KW - Glucocorticoid receptor
KW - Hippocampus
KW - Medial prefrontal cortex
KW - Mineralocorticoid receptor
KW - Serotonin transporter
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U2 - 10.3389/fnbeh.2014.00355
DO - 10.3389/fnbeh.2014.00355
M3 - Article
AN - SCOPUS:84907963640
SN - 1662-5153
VL - 8
SP - 1
EP - 11
JO - Frontiers in Behavioral Neuroscience
JF - Frontiers in Behavioral Neuroscience
IS - OCT
M1 - 355
ER -