6403
2011
eng
article
1
2013-02-05
--
--
Differential Effects of Prenatal Stress in 5-Htt Deficient Mice: Towards Molecular Mechanisms of Gene x Environment Interactions
Prenatal stress (PS) has been shown to influence the development of the fetal brain and to increase the risk for the development of psychiatric disorders in later life. Furthermore, the variation of human serotonin transporter (5-HTT, SLC6A4) gene was suggested to exert a modulating effect on the association between early life stress and the risk for depression. In the present study, we used a 5-Htt6PS paradigm to investigate whether the effects of PS are dependent on the 5-Htt genotype. For this purpose, the effects of PS on cognition, anxiety- and depression-related behavior were examined using a maternal restraint stress paradigm of PS in C57BL6 wild-type (WT) and heterozygous 5-Htt deficient (5-Htt +/2) mice. Additionally, in female offspring, a genome-wide hippocampal gene expression profiling was performed using the Affymetrix GeneChipH Mouse Genome 430 2.0 Array. 5-Htt +/2 offspring showed enhanced memory performance and signs of reduced anxiety as compared to WT offspring. In contrast, exposure of 5-Htt +/2 mice to PS was associated with increased depressive-like behavior, an effect that tended to be more pronounced in female offspring. Further, 5-Htt genotype, PS and their interaction differentially affected the expression of numerous genes and related pathways within the female hippocampus. Specifically, MAPK and neurotrophin signaling were regulated by both the 5-Htt +/2 genotype and PS exposure, whereas cytokine and Wnt signaling were affected in a 5-Htt genotype6PS manner, indicating a gene6environment interaction at the molecular level. In conclusion, our data suggest that although the 5-Htt +/2 genotype shows clear adaptive capacity, 5-Htt +/2 mice –particularly females– at the same time appear to be more vulnerable to developmental stress exposure when compared to WT offspring. Moreover, hippocampal gene expression profiles suggest that distinct molecular mechanisms mediate the behavioral effects of the 5-Htt genotype, PS exposure, and their interaction.
urn:nbn:de:bvb:20-opus-75795
7579
In: PLoS ONE (2011) 6(8): e22715. doi:10.1371/journal.pone.0022715
Daniel Van den Hove
Sissi Brigitte Jakob
Karla-Gerlinde Schraut
Gunter Kenis
Angelika Gertrud Schmitt
Susanne Kneitz
Claus-Jürgen Scholz
Valentina Wiescholleck
Gabriela Ortega
Jos Prickaerts
Harry Steinbusch
Klaus-Peter Lesch
deu
swd
Medizin
Medizin und Gesundheit
open_access
Theodor-Boveri-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/6403/vandenHove_journal.pone.0022715.pdf
13511
2011
eng
e22715
8
6
article
1
2016-06-17
--
--
Differential Effects of Prenatal Stress in 5-Htt Deficient Mice: Towards Molecular Mechanisms of Gene x Environment Interactions
Prenatal stress (PS) has been shown to influence the development of the fetal brain and to increase the risk for the development of psychiatric disorders in later life. Furthermore, the variation of human serotonin transporter (5-HTT, SLC6A4) gene was suggested to exert a modulating effect on the association between early life stress and the risk for depression. In the present study, we used a 5-HttxPS paradigm to investigate whether the effects of PS are dependent on the 5-Htt genotype. For this purpose, the effects of PS on cognition, anxiety-and depression-related behavior were examined using a maternal restraint stress paradigm of PS in C57BL6 wild-type (WT) and heterozygous 5-Htt deficient (5-Htt +/-) mice. Additionally, in female offspring, a genome-wide hippocampal gene expression profiling was performed using the Affymetrix GeneChip (R) Mouse Genome 430 2.0 Array. 5-Htt +/- offspring showed enhanced memory performance and signs of reduced anxiety as compared to WT offspring. In contrast, exposure of 5-Htt +/- mice to PS was associated with increased depressive-like behavior, an effect that tended to be more pronounced in female offspring. Further, 5-Htt genotype, PS and their interaction differentially affected the expression of numerous genes and related pathways within the female hippocampus. Specifically, MAPK and neurotrophin signaling were regulated by both the 5-Htt +/- genotype and PS exposure, whereas cytokine and Wnt signaling were affected in a 5-Htt genotypexPS manner, indicating a genexenvironment interaction at the molecular level. In conclusion, our data suggest that although the 5-Htt +/- genotype shows clear adaptive capacity, 5-Htt +/- mice -particularly females-at the same time appear to be more vulnerable to developmental stress exposure when compared to WT offspring. Moreover, hippocampal gene expression profiles suggest that distinct molecular mechanisms mediate the behavioral effects of the 5-Htt genotype, PS exposure, and their interaction.
PLoS ONE
10.1371/journal.pone.0022715
urn:nbn:de:bvb:20-opus-135111
PLoS ONE 6(8): e22715. doi:10.1371/journal.pone.0022715
false
true
Daniel Van den Hove
Sissi Brigitte Jakob
Karla-Gerlinde Schraut
Gunter Kenis
Angelika Gertrud Schmitt
Susanne Kneitz
Claus-Jürgen Scholz
Valentina Wiescholleck
Gabriela Ortega
Jos Prickaerts
Harry Steinbusch
Klaus-Peter Lesch
eng
uncontrolled
Serotonin transporter polymorphism
eng
uncontrolled
Acute tryptophan depletion
eng
uncontrolled
Anxiety-like behavior
eng
uncontrolled
Long-term depression
eng
uncontrolled
Knock-out mice
eng
uncontrolled
Major depression
eng
uncontrolled
Interferon-alpha
eng
uncontrolled
Physiological functions
eng
uncontrolled
Restraint stress
eng
uncontrolled
Bipolar disorder
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/13511/036_vandenHove_PlosONE.PDF