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When the Serotonin Transporter Gene Meets Adversity: The Contribution of Animal Models to Understanding Epigenetic Mechanisms in Affective Disorders and Resilience

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Molecular and Functional Models in Neuropsychiatry

Part of the book series: Current Topics in Behavioral Neurosciences ((CTBN,volume 7))

Abstract

Although converging epidemiological evidence links exposure to stressful life events with increased risk for affective spectrum disorders, there is extraordinary interindividual variability in vulnerability to adversity. The environmentally moderated penetrance of genetic variation is thought to play a major role in determining who will either develop disease or remain resilient. Research on genetic factors in the aetiology of disorders of emotion regulation has, nevertheless, been complicated by a mysterious discrepancy between high heritability estimates and a scarcity of replicable gene-disorder associations. One explanation for this incongruity is that at least some specific gene effects are conditional on environmental cues, i.e. gene-by-environment interaction (G × E) is present. For example, a remarkable number of studies reported an association of variation in the human serotonin (5-HT) transporter gene (SLC6A4, 5-HTT, SERT) with emotional and cognitive traits as well as increased risk for depression in interaction with psychosocial adversity. The results from investigations in non-human primate and mouse support the occurrence of G × E interaction by showing that variation of 5-HTT function is associated with a vulnerability to adversity across the lifespan leading to unfavourable outcomes resembling various neuropsychiatric disorders. The neural and molecular mechanisms by which environmental adversity in early life increases disease risk in adulthood are not known but may include epigenetic programming of gene expression during development. Epigenetic mechanisms, such as DNA methylation and chromatin modification, are dynamic and reversible and may also provide targets for intervention strategies (see Bountra et al., Curr Top Behav Neurosci, 2011). Animal models amenable to genetic manipulation are useful in the identification of molecular mechanisms underlying epigenetic programming by adverse environments and individual differences in resilience to stress. Therefore, deeper insight into the role of epigenetic regulation in the process of neurodevelopmental programmes is likely to result in early diagnosis of affective spectrum disorders and will contribute to the design of innovative treatments targeting neural pathways that foster resilience.

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Abbreviations

5-HIAA:

5-Hydroxyindoleacidic acid

5-HT:

Serotonin

5-HTT:

Serotonin transporter

5-HTTLPR:

5-HTT gene-linked polymorphic region

ACTH:

Adrenocorticotropic hormone

BDNF:

Brain-derived neurotrophic factor

CRH:

Corticotropin-releasing hormone

CSF:

Cerebrospinal fluid

G × E:

Gene-by-environment interactions

GABA-A:

Gamma-aminobutyric acid-A receptor

GR:

Glucocorticoid receptor

HDAC:

Histone deacetylase inhibitor

HPA:

Hypothalamic–pituitary–adrenal

MRI:

Magnetic resonance imaging

MS:

Maternal separation

OFC:

Orbitofrontal cortex

rh5-HTTLPR:

Rhesus macaque 5-HTT gene-linked polymorphic region

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Acknowledgement

The work by the author is supported by the DFG (KFO 125, SFB 581/B9, SFB TRR 58/A1 and A5), BMBF (IZKF Wuerzburg, 01KS9603) and the EC (NEWMOOD LSHM-CT-2003-503474).

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  1. Molecular Psychiatry, ADHD Clinical Research Network, Laboratory of Translational Neuroscience, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Fuechsleinstr. 15, 97080, Wuerzburg, Germany

    Klaus-Peter Lesch

  2. Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, European Graduate School for Neuroscience (EURON), Maastricht University, 616, 6200 MD, Maastricht, The Netherlands

    Klaus-Peter Lesch

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  1. Klaus-Peter Lesch
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Correspondence to Klaus-Peter Lesch .

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  1. Global Medical Excellence Cluster (GMEC), King's College London, London, SE1 1UL, United Kingdom

    Jim J. Hagan

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Lesch, KP. (2011). When the Serotonin Transporter Gene Meets Adversity: The Contribution of Animal Models to Understanding Epigenetic Mechanisms in Affective Disorders and Resilience. In: Hagan, J. (eds) Molecular and Functional Models in Neuropsychiatry. Current Topics in Behavioral Neurosciences, vol 7. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7854_2010_109

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