Sex Modulates the Interactive Effect of the Serotonin Transporter Gene Polymorphism and Childhood Adversity on Hippocampal Volume

Everaerd, Daphne; Gerritsen, Lotte; Rijpkema, Mark; Frodl, Thomas; Oostrom, van; Franke, Barbara; Fernández, Guillén; Tendolkar, Indira

doi:10.1038/npp.2012.32

Cited by 49 publications

(48 citation statements)

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“…Here we show that these early-life stress effects are markedly modulated by sex, potentially via sex-specific compensatory mechanisms in response to CRH hyper-signaling. Accumulating evidence supports the importance of sex differences in the neurobiological consequences of stress pathway activation during development and response to trauma (De Bellis and Keshavan, 2003;Everaerd et al, 2012).…”

Section: Discussionmentioning

confidence: 96%

Overexpression of Forebrain CRH During Early Life Increases Trauma Susceptibility in Adulthood

Tóth

Flandreau

Deslauriers

et al. 2015

Neuropsychopharmacol

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Although early-life stress is a significant risk factor for developing anxiety disorders, including posttraumatic stress disorder (PTSD), the underlying mechanisms are unclear. Corticotropin releasing hormone (CRH) is disrupted in individuals with PTSD and early-life stress and hence may mediate the effects of early-life stress on PTSD risk. We hypothesized that CRH hyper-signaling in the forebrain during early development is sufficient to increase response to trauma in adulthood. To test this hypothesis, we induced transient, forebrain-specific, CRH overexpression during early-life (pre-puberty, CRHOE dev ) in double-mutant mice (Camk2a-rtta2 × tetO-Crh) and tested their behavioral and gene expression responses to the predator stress model of PTSD in adulthood. In one cohort of CRHOE dev exposed and unexposed mice, avoidance and arousal behaviors were examined 7-15 days after exposure to predator stress. In another cohort, gene expression changes in Crhr1, Crhr2, and Fkbp51 in forebrain of CRHOE dev exposed and unexposed mice were examined 7 days after predator stress. CRHOE dev induced robust increases in startle reactivity and reductions in startle inhibition independently of predator stress in both male and female mice. Avoidance behaviors after predator stress were highly dependent on sex and CRHOE dev exposure. Whereas stressed females exhibited robust avoidance responses that were not altered by CRHOE dev , males developed significant avoidance only when exposed to both CRHOE dev and stress. Quantitative real-time-PCR analysis indicated that CRHOE dev unexposed males exhibit significant changes in Crhr2 expression in the amygdala and bed nucleus stria terminalis in response to stress, whereas males exposed to CRHOE dev did not. Similar to CRHOE dev males, females exhibited no significant Crhr2 gene expression changes in response to stress. Cortical Fkbp51 expression was also significantly reduced by stress and CRHOE dev exposure in males, but not in females. These findings indicate that forebrain CRH hyper-signaling in early-life is sufficient to increase enduring effects of adult trauma and attenuate Crhr2 expression changes in response to stress in males. These data support growing evidence for significant sex differences in response to trauma, and support further study of CRHR2 as a candidate mechanism for PTSD risk.

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Section: Discussionmentioning

confidence: 96%

Overexpression of Forebrain CRH During Early Life Increases Trauma Susceptibility in Adulthood

Tóth

Flandreau

Deslauriers

et al. 2015

Neuropsychopharmacol

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“…Another reason could be a gender difference in genetic modulation of depression by 5-HTTLPR. A gender-specific genetic effect has been reported for 5-HTTLPR in many psychiatric phenotypes, particularly in terms of the interaction with an environmental effect 28,29. It is possible that the genetic effect is moderated in a gender-specific way.…”

Section: Discussionmentioning

confidence: 99%

Genetic Role of BDNF Val66Met and 5-HTTLPR Polymorphisms on Depressive Disorder

Lee

Jeong

Kim

et al. 2014

Psychiatry Investig

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ObjectiveWe investigated possible association between depressive disorders and BDNF Val66Met and 5-HTTLPR. Brain derived neurotrophic factor (BDNF) gene and serotonin transporter (SLC6A4) gene are promising candidate genes for depressive disorders. It has been suggested that BDNF promotes the survival and differentiation of serotonergic neurons and that serotonergic transmission exerts powerful control over BDNF gene expression.MethodsFinal analyses were performed on 186 patients with depressive disorders and 1032 controls. Val66Met polymorphism of BDNF gene and 5-HTTLPR polymorphism of serotonin transporter gene were genotyped and allele and genotypic associations on the diagnosis of depression and age at onset of depression were analyzed.ResultsThe 5-HTTLPR was positively associated with depressive affected status in the total sample and in females (p=0.038 for allelewise, p=0.015 for genotype-wise associations), but, not in males. The BDNF Val66Met showed no association with depression. BDNF Val66Met and 5-HTTLPR alone were not associated with age at onset of depression. Additional analysis on the interaction between BDNF Val66Met and 5-HTTLPR found a significant association with age at onset of depression in the entire patient group. This association was also found in the female but not in the male patient group. None of the positive results survived Bonferroni correction for multiple testing.ConclusionThis result suggested that BDNF Val66Met and 5-HTTLPR may contribute to depressive disorders in a complex way and that the genetic effect could differ by gender. Further studies with large number of patients will be necessary.

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“…Smaller hippocampal volumes represent putative structural endophenotypes for PTSD, as observed in MRI studies of 5-HTTLPR , BDNF , and FKBP5 (Gatt et al, 2009; Frodl et al, 2010; Eker et al, 2011; Everaerd et al, 2012; Carballedo et al, 2013; Fani et al, 2013), with some of these findings reflecting gene by environment (e.g. childhood maltreatment) interactions (Gatt et al, 2009; Everaerd et al, 2012; Carballedo et al, 2013).…”

Section: Neuroimaging Geneticsmentioning

confidence: 94%

“…Indeed, one study found this pattern of activation to be particularly apparent in males with SS genotype who reported higher exposure to potentially traumatic experiences (Alexander et al, 2012). Some structural studies have likewise indicated that the S-allele may represent ‘risk’ for lower hippocampal volume (Eker et al, 2011), particularly in combination with childhood abuse history (Frodl et al, 2010; Everaerd et al, 2012); however, this finding has not been uniform across all studies (Cole et al, 2011). …”

Section: Neuroimaging Geneticsmentioning

confidence: 99%

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Genetic approaches to understanding post-traumatic stress disorder

Almli¹,

Fani²,

Smith³

et al. 2013

Int. J. Neuropsychopharm.

100

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Post-traumatic stress disorder (PTSD) is increasingly recognized as both a disorder of enormous mental health and societal burden, but also as an anxiety disorder that may be particularly understandable from a scientific perspective. Specifically, PTSD can be conceptualized as a disorder of fear and stress dysregulation, and the neural circuitry underlying these pathways in both animals and humans are becoming increasingly well understood. Furthermore, PTSD is the only disorder in psychiatry in which the initiating factor, the trauma exposure, can be identified. Thus, the pathophysiology of the fear and stress response underlying PTSD can be examined and potentially interrupted. Twin studies have shown that the development of PTSD following a trauma is heritable, and that genetic risk factors may account for up to 30–40% of this heritability. A current goal is to understand the gene pathways that are associated with PTSD, and how those genes act on the fear/stress circuitry to mediate risk vs. resilience for PTSD. This review will examine gene pathways that have recently been analysed, primarily through candidate gene studies (including neuroimaging studies of candidate genes), in addition to genome-wide associations and the epigenetic regulation of PTSD. Future and on-going studies are utilizing larger and collaborative cohorts to identify novel gene candidates through genome-wide association and other powerful genomic approaches. Identification of PTSD biological pathways strengthens the hope of progress in the mechanistic understanding of a model psychiatric disorder and allows for the development of targeted treatments and interventions.

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Sex Modulates the Interactive Effect of the Serotonin Transporter Gene Polymorphism and Childhood Adversity on Hippocampal Volume

Cited by 49 publications

References 49 publications

Overexpression of Forebrain CRH During Early Life Increases Trauma Susceptibility in Adulthood

Overexpression of Forebrain CRH During Early Life Increases Trauma Susceptibility in Adulthood

Genetic Role of BDNF Val66Met and 5-HTTLPR Polymorphisms on Depressive Disorder

Genetic approaches to understanding post-traumatic stress disorder

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