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.
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 o...
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| Format: | Article |
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Frontiers Media S.A.
2014-10-01
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| Series: | Frontiers in Behavioral Neuroscience |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fnbeh.2014.00355/full |
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| author | Rick H. A. Van der Doelen Francesca eCalabrese Gianluigi eGuidotti Bram eGeenen Marco A. Riva Tamas eKozicz Judith R. Homberg |
| author_facet | Rick H. A. Van der Doelen Francesca eCalabrese Gianluigi eGuidotti Bram eGeenen Marco A. Riva Tamas eKozicz Judith R. Homberg |
| author_sort | Rick H. A. Van der Doelen |
| collection | DOAJ |
| description | 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 receptor (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 x 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. |
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| institution | Directory Open Access Journal |
| issn | 1662-5153 |
| language | English |
| last_indexed | 2024-12-23T06:50:55Z |
| publishDate | 2014-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Behavioral Neuroscience |
| spelling | doaj.art-f3301eca73f945f69a081ca054e5d5932022-12-21T17:56:27ZengFrontiers Media S.A.Frontiers in Behavioral Neuroscience1662-51532014-10-01810.3389/fnbeh.2014.00355109387Early 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 Doelen0Francesca eCalabrese1Gianluigi eGuidotti2Bram eGeenen3Marco A. Riva4Tamas eKozicz5Judith R. Homberg6Radboud University Nijmegen Medical CenterUniversità degli Studi di MilanoUniversità degli Studi di MilanoRadboud University Nijmegen Medical CenterUniversità degli Studi di MilanoRadboud University Nijmegen Medical CenterRadboud University Nijmegen Medical CenterThe 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 receptor (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 x 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.http://journal.frontiersin.org/Journal/10.3389/fnbeh.2014.00355/fullDepressionHippocampusserotonin transporterearly life stressGlucocorticoid receptormineralocorticoid receptor |
| spellingShingle | Rick H. A. Van der Doelen Francesca eCalabrese Gianluigi eGuidotti Bram eGeenen Marco A. Riva Tamas eKozicz Judith R. Homberg 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. Frontiers in Behavioral Neuroscience Depression Hippocampus serotonin transporter early life stress Glucocorticoid receptor mineralocorticoid receptor |
| 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. |
| title_full | 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. |
| title_fullStr | 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. |
| title_full_unstemmed | 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. |
| title_short | 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. |
| title_sort | 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 |
| topic | Depression Hippocampus serotonin transporter early life stress Glucocorticoid receptor mineralocorticoid receptor |
| url | http://journal.frontiersin.org/Journal/10.3389/fnbeh.2014.00355/full |
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