Serotonin transporter knockout and repeated social defeat stress: Impact on neuronal morphology and plasticity in limbic brain areas

Nietzer, SL; Bonn, M.; Jansen, Friederike; Heiming, Rebecca S.; Lewejohann, Lars; Sachser, Norbert; Asan, Esther; Lesch, Klaus‐Peter; Schmitt, Angelika

doi:10.1016/j.bbr.2011.01.011

Cited by 50 publications

(43 citation statements)

References 94 publications

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“…An investigation into the effect of chronic work stressors on a nurse cohort showed that increased DNA methylation at the promoter region of SLC6A4 was associated with a higher level of burnout (Alasaari et al, 2012). These studies are in line with clinical studies that have linked reduced expression of SLC6A4 , by its promoter length polymorphism, with elevated stress reactivity (Miller et al, 2013) and with depression (Caspi et al, 2003; Karg et al, 2011; Nietzer et al, 2011; Kenna et al, 2012), though the latter point remains unsettled (Risch et al, 2009; Culverhouse et al, 2013). …”

Section: Introductionsupporting

confidence: 82%

“…Individuals who express low levels of serotonin transporter have been observed to exhibit higher amygdala activity than those who express higher levels (Hariri et al, 2002; Heinz et al, 2005). Similarly, artificially reducing serotonin transporter expression by knocking out the SLC6A4 gene in mice resulted in increased amygdaloid neuronal spine density which is presumed to be a morphological manifestation of enhanced synaptic connectivity and activity of the amygdala (Nietzer et al, 2011). These mice also display an anxiety-like phenotype (Line et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Effects of negative stressors on DNA methylation in the brain: Implications for mood and anxiety disorders

Hing

Gardner

Potash

2014

American J of Med Genetics Pt B

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Stress is a major contributor to anxiety and mood disorders. The recent discovery of epigenetic changes in the brain resulting from stress has enhanced our understanding of the mechanism by which stress is able to promote these disorders. Although epigenetics encompasses chemical modifications that occur at both DNA and histones, much attention has been focused on stress-induced DNA methylation changes on behavior. Here, we review the effect of stress-induced DNA methylation changes on physiological mechanisms that govern behavior and cognition, dysregulation of which can be harmful to mental health. A literature review was performed in the areas of DNA methylation, stress, and their impact on the brain and psychiatric illness. Key findings center on genes involved in the hypothalamic-pituitary-adrenal axis, neurotransmission and neuroplasticity. Using animal models of different stress paradigms and clinical studies, we detail how DNA methylation changes to these genes can alter physiological mechanisms that influence behavior. Appropriate levels of gene expression in the brain play an important role in mental health. This dynamic control can be disrupted by stress-induced changes to DNA methylation patterns. Advancement in other areas of epigenetics, such as histone modifications and the discovery of the novel DNA epigenetic mark, 5-hydroxymethylcytosine, could provide additional avenues to consider when determining the epigenetic effects of stress on the brain.

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Section: Introductionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Effects of negative stressors on DNA methylation in the brain: Implications for mood and anxiety disorders

Hing

Gardner

Potash

2014

American J of Med Genetics Pt B

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“…As such, perinatal Flx exposure could affect any of the neurodevelopmental processes typically regulated by serotonin. In fact, serotonin transporter knockout mice show alterations in the neuronal morphology of the limbic system [38,39]. …”

Section: Discussionmentioning

confidence: 99%

“…All of these behaviours are, at least in part, modulated by serotonin. Both monoamine oxidase A (humans [31]; animals [32,33,34]) and serotonin transporter dysfunction (humans [35,36,37]; animals [38,39]) increase serotonin during development and lead to changes in the aforementioned behaviours, particularly anxiety and aggression. …”

Section: Introductionmentioning

confidence: 99%

Increased Aggression, Improved Spatial Memory, and Reduced Anxiety-Like Behaviour in Adult Male Mice Exposed to Fluoxetine Early in Life

Kiryanova

Dyck

2014

Dev Neurosci

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Rationale: Fluoxetine (Flx; brand names Prozac, Sarafem, Rapiflux), a selective serotonin reuptake inhibitor, is prescribed for the treatment of depression in pregnant women; however, this commonly prescribed medication could affect fetal brain development as Flx crosses the placenta. The available data concerning the anatomical and behavioural consequences of perinatal exposure to Flx during early development on adult behaviour are limited and often contradictory. Objectives: To further delineate the long-term behavioural effects of altering 5-HT during development, we examined the effects of perinatal Flx exposure on the behaviour of male mice as adults. Methods: Dams were treated with approximately 25 mg/kg/day of Flx from embryonic day 15 to postnatal day 12, and the behaviour of the adult offspring was assessed. Results: We found that perinatal Flx exposure leads to increased aggression, improved spatial memory, and reduced anxiety-like behaviour. This exposure did not cause memory deficits, changes in sensory processing, or changes in gross motor function. Conclusions: Our results suggest that while perinatal exposure to Flx may have long-term effects on adult behaviour, these effects appear limited and not necessarily detrimental.

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“…The impaired extinction of negative events could easily lead to the development of long-lasting fear associations. Accordingly, life-long reduced SERT expression is related to altered neuronal morphology (e.g., density of dendrites and dendritic spines) in key regions of the cortico-limbic circuitry mediating emotion processing (e.g., prefrontal cortex, specific nuclei of the amygdala) ( [48,59]; Wotjak and Pape, this edition). Furthermore, the extinction learning of an individual, which developed on the basis of the SERT genotype and the negative experiences made during development is directly reflected in the synchronization of oscillating brain waves between the amygdala and the prefrontal cortex [47].…”

Section: Underlying Mechanismsmentioning

confidence: 99%

The interplay of genotype and environment in the development of fear and anxiety

Sachser

Lesch

2013

E-Neuroforum

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Individual differences in fear, anxiety, and the etiology of anxiety disorders develop during ontogeny. They are due to both genetic and environmental factors. With regard to the role of the environment, the organism is most susceptible to external influences during early development. Accordingly, stressors that impinge on the maternal organism during pregnancy evoke high levels of anxiety in the offspring later in life, as does an adverse early postnatal environment. However, anxiety-related circuits in the central nervous system retain their plasticity in adulthood, i.e., levels of anxiety can also be modified by experience across the entire successive lifespan. Notably, the effects of external stressors on the individual’s level of anxiety are modulated by genotype. Such genotype-by-environment interactions are particularly well studied in relation to genetic variants that modulate the function of the serotonin transporter. Thus, this review focuses on this candidate gene to elucidate the interplay of genotype and environment in the development of fear and anxiety.

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Serotonin transporter knockout and repeated social defeat stress: Impact on neuronal morphology and plasticity in limbic brain areas

Cited by 50 publications

References 94 publications

Effects of negative stressors on DNA methylation in the brain: Implications for mood and anxiety disorders

Effects of negative stressors on DNA methylation in the brain: Implications for mood and anxiety disorders

Increased Aggression, Improved Spatial Memory, and Reduced Anxiety-Like Behaviour in Adult Male Mice Exposed to Fluoxetine Early in Life

The interplay of genotype and environment in the development of fear and anxiety

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