Serotonin transporter gene methylation is associated with hippocampal gray matter volume

Dannlowski, Udo; Kugel, Harald; Redlich, Ronny; Halik, Adriane; Schneider, Ilona; Opel, Nils; Grotegerd, Dominik; Schwarte, Kathrin; Schettler, Christiane; Ambrée, Oliver; Rust, Stephan; Domschke, Katharina; Arolt, Volker; Heindel, Walter; Baune, Bernhard T.; Suslow, Thomas; Zhang, Weiqi; Hohoff, Christa

doi:10.1002/hbm.22555

Cited by 56 publications

(37 citation statements)

References 84 publications

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“…Interestingly, hippocampal GMV was previously associated with another serotonergic measure, 5-HT transporter gene methylation status, in humans (Dannlowski et al 2014). Furthermore, brain fibroblast growth factor receptor 1 (FGFR1)-5-HT 1A heteroreceptor complexes, and their enhancement of neuro-plasticity, were first described in the hippocampus (Borroto-Escuela et al 2016), where 5-HT 1A receptors may promote greater GMV, potentially protecting HCs against depression (Schmidt and Duman 2007).…”

Section: Postsynaptic 5-ht1a Receptors Binding and Gmv In The Terminamentioning

confidence: 96%

In vivo relationship between serotonin 1A receptor binding and gray matter volume in the healthy brain and in major depressive disorder

et al. 2018

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Serotonin 1A (5-HT) receptors mediate serotonin trophic role in brain neurogenesis. Gray matter volume (GMV) loss and 5-HT receptor binding alterations have been identified in major depressive disorder (MDD). Here we investigated the relationship between 5-HT receptor binding and GMV in 40 healthy controls (HCs) and, for the first time, 47 antidepressant-free MDD patients using Voxel-Based Morphometry and [C]WAY100635 Positron Emission Tomography. Values of GMV and 5-HT binding (expressed as BP, one of the types of binding potentials that refer to displaceable or specific binding that can be quantified in vivo with PET) were obtained in 13 regions of interest, including raphe, and at the voxel level. We used regression analysis within each group to predict GMV from BP, while covarying for age, sex, total gray matter volume and medication status. In the HCs group, we found overall a positive correlation between terminal field 5-HT receptor binding and GMV, which reached statistical significance in regions such as hippocampus, insula, orbital prefrontal cortex, and parietal lobe. We observed a trend towards inverse correlation between raphe 5-HT autoreceptor binding and anterior cingulate GMV in both groups, and a statistically significant positive correlation between raphe 5-HT binding and temporal GMV in MDD. Analysis of covariance at the voxel-level revealed a trend towards interaction between diagnosis and raphe 5-HT binding in predicting GMV in cerebellum and supramarginal gyrus (higher correlation in HCs compared with MDD). Our results replicated previous findings in the normative brain, but did not extend them to the brain in MDD, and indicated a trend towards dissociation between MDD and HCs in the relationship of raphe 5-HT binding with postsynaptic GMV. These results suggest that 5-HT receptors contribute to altered neuroplasticity in MDD, possibly via effects predating depression onset.

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Section: Postsynaptic 5-ht1a Receptors Binding and Gmv In The Terminamentioning

confidence: 96%

In vivo relationship between serotonin 1A receptor binding and gray matter volume in the healthy brain and in major depressive disorder

et al. 2018

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“…In concert, the emerging genetic and genomic findings in PTSD implicate molecular pathways that might alter hippocampal-prefrontal-thalamic circuitry – perhaps impacting hippocampal volume or context-relevant hippocampal function like neurogenesis and LTP. For example, polymorphisms in BDNF (Gatt et al, 2009; Aas et al, 2014), ADBR2 and FKBP5 (Fani et al, 2013), or methylation of SLC6A4 (Dannlowski et al, 2014) or FKBP5 (Fani et al, 2013) , all have hippocampal effects, and each has evidence for association with PTSD. These findings resonate with reports of hippocampal size differences seen in PTSD, which may constitute a risk factor for PTSD development (Gilbertson et al, 2002; Bremner et al, 2003; Kitayama et al, 2005).…”

Section: A New Model: Deficient Context Processingmentioning

confidence: 99%

Context Processing and the Neurobiology of Post-Traumatic Stress Disorder

Liberzon

Abelson

2016

Neuron

361

335

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Summary Progress in clinical and affective neuroscience is redefining psychiatric illness as symptomatic expression of cellular/molecular dysfunctions in specific brain circuits. Post-traumatic stress disorder (PTSD) has been an exemplar of this progress, with improved understanding of neurobiological systems subserving fear learning, salience detection, and emotion regulation explaining much of its phenomenology and neurobiology. However, many features remain unexplained and a parsimonious model that more fully accounts for symptoms and the core neurobiology remains elusive. Contextual processing is a key modulatory function of hippocampal-prefrontal-thalamic circuitry, allowing organisms to disambiguate cues and derive situation-specific meaning from the world. We propose that dysregulation within this context-processing circuit is at the core of PTSD pathophysiology, accounting for much of its phenomenology and most of its biological findings. Understanding core mechanisms like this, and their underlying neural circuits, will sharpen diagnostic precision and understanding of risk factors, enhancing our ability to develop preventive and “personalized” interventions.

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“…Indeed, the potential impact of methylation on human brain function has been recently demonstrated (Booij et al, 2015;Dannlowski et al, 2014;Frodl et al, 2015;Klengel et al, 2013;Nikolova and Hariri, in press;Nikolova et al, 2014;Ziegler et al, 2015). For instance, methylation within the serotonin transporter gene predicts increased threat-related amygdala reactivity as well as decreased SLC6A4 expression in postmortem brain tissue (Nikolova et al, 2014).…”

Section: Mechanistic Understandingmentioning

confidence: 99%

Genetic Moderation of Stress Effects on Corticolimbic Circuitry

Bogdan

Pagliaccio

Baranger

et al. 2015

Neuropsychopharmacol

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Stress exposure is associated with individual differences in corticolimbic structure and function that often mirror patterns observed in psychopathology. Gene x environment interaction research suggests that genetic variation moderates the impact of stress on risk for psychopathology. On the basis of these findings, imaging genetics, which attempts to link variability in DNA sequence and structure to neural phenotypes, has begun to incorporate measures of the environment. This research paradigm, known as imaging gene x environment interaction (iGxE), is beginning to contribute to our understanding of the neural mechanisms through which genetic variation and stress increase psychopathology risk. Although awaiting replication, evidence suggests that genetic variation within the canonical neuroendocrine stress hormone system, the hypothalamic-pituitary-adrenal axis, contributes to variability in stress-related corticolimbic structure and function, which, in turn, confers risk for psychopathology. For iGxE research to reach its full potential it will have to address many challenges, of which we discuss: (i) small effects, (ii) measuring the environment and neural phenotypes, (iii) the absence of detailed mechanisms, and (iv) incorporating development. By actively addressing these challenges, iGxE research is poised to help identify the neural mechanisms underlying genetic and environmental associations with psychopathology.

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Serotonin transporter gene methylation is associated with hippocampal gray matter volume

Cited by 56 publications

References 84 publications

In vivo relationship between serotonin 1A receptor binding and gray matter volume in the healthy brain and in major depressive disorder

In vivo relationship between serotonin 1A receptor binding and gray matter volume in the healthy brain and in major depressive disorder

Context Processing and the Neurobiology of Post-Traumatic Stress Disorder

Genetic Moderation of Stress Effects on Corticolimbic Circuitry

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