title: Differential effects of prenatal stress in 5-Htt deficient mice: towards molecular mechanisms of gene × environment interactions.
abstract: 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-Htt×PS 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® 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 genotype×PS manner, indicating a gene×environment 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.
authors.affiliation: Institute of Molecular Psychiatry, Laboratory of Translational Neuroscience, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany. d.vandenhove@maastrichtuniversity.nl
authors.forename: Daniel Louis Albert
authors.initials: DL
authors.lastname: van den Hove
authors.forename: Daniel
authors.initials: D
authors.lastname: Van den Hove
authors.forename: Sissi Brigitte
authors.initials: SB
authors.lastname: Jakob
authors.forename: Karla-Gerlinde
authors.initials: KG
authors.lastname: Schraut
authors.forename: Gunter
authors.initials: G
authors.lastname: Kenis
authors.forename: Angelika Gertrud
authors.initials: AG
authors.lastname: Schmitt
authors.forename: Susanne
authors.initials: S
authors.lastname: Kneitz
authors.forename: Claus-Jürgen
authors.initials: CJ
authors.lastname: Scholz
authors.forename: Valentina
authors.initials: V
authors.lastname: Wiescholleck
authors.forename: Gabriela
authors.initials: G
authors.lastname: Ortega
authors.forename: Jos
authors.initials: J
authors.lastname: Prickaerts
authors.forename: Harry
authors.initials: H
authors.lastname: Steinbusch
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001007:Anxiety / Q000503:physiopathology / Q000523:psychology; D003071:Cognition / Q000502:physiology; D003345:Corticosterone / Q000097:blood; D003863:Depression / Q000503:physiopathology / Q000523:psychology; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D059647:Gene-Environment Interaction; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D008568:Memory / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D011247:Pregnancy; D011597:Psychomotor Performance / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050486:Serotonin Plasma Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics; D012737:Sex Factors; D013315:Stress, Psychological / Q000097:blood / Q000503:physiopathology* / Q000523:psychology; D059467:Transcriptome
chemical_list: D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D003345:Corticosterone