Seasonal Changes in Brain Serotonin Transporter Binding in Short Serotonin Transporter Linked Polymorphic Region-Allele Carriers but Not in Long-Allele Homozygotes

Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
Biological psychiatry (Impact Factor: 10.26). 06/2010; 67(11):1033-9. DOI: 10.1016/j.biopsych.2009.11.027
Source: PubMed


A polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) has been associated with seasonality both in patients with seasonal affective disorder and in the general population.
We used in vivo molecular imaging to measure cerebral serotonin transporter (5-HTT) binding in 57 healthy Scandinavians and related the outcome to season of the year and to the 5-HTTLPR carrier status.
We found that the number of daylight minutes at the time of scanning correlated negatively with 5-HTT binding in the putamen and the caudate, with a similar tendency in the thalamus, whereas this association was not observed for the midbrain. Furthermore, in the putamen, an anatomic region with relatively dense serotonin innervation, we found a significant gene x daylight effect, such that there was a negative correlation between 5-HTT binding and daylight minutes in carriers of the short 5-HTTLPR allele but not in homozygote carriers of the long allele.
Our findings are in line with S-carriers having an increased response in neural circuits involved in emotional processing to stressful environmental stimuli but here demonstrated as a endophenotype with dynamic changes in serotonin reuptake.

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    • "In the human brain, SAD manifests itself as a mental condition characterized by a phasic occurrence of major depression during wintertime and with subsequent remission in summertime [1]. It is hypothesized to be in part triggered by a seasonal misregulation of the serotonin transporter (SERT), the mechanism by which endogenous serotonin (5-HT) is inactivated and recycled into the presynaptic terminal [2] [4]. These fluctuations are particularly evident in carriers of the short 5-HTTLPR polymorphism (S-allele carriers). "
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    ABSTRACT: The purpose of this study was to assess the ability of the newly developed FreeSurfer (FS) PET processing pipeline to reproduce the results reported by Mc Mahon et al. 2014. Mc Mahon et al. 2014 investigated differences of the serotonin transporter (SERT) between summer and winter scans in patients suffering from Seasonal Affective Disorder (SAD) versus healthy controls, and for various genotypes. Seventeen SAD patients (8 men, 9 women; age, 27 ± 9 y) and 23 healthy controls (10 men, 13 women; age, 25 ± 7 y) underwent [ 11 C]-DASB PET imaging two consecutive times in a randomized sequence (winter or summer), defined by a 12 week interval centered around winter or summer solstice. A global volume weighted non-displacable binding potential (BPND) was estimated for all patients with the purpose of evaluating seasonal variation at the group level. We intended to evaluate reproducibility and consistency of the results reported by Mc Mahon et al. 2014 by comparing the corresponding results obtained with the newly developed FS PET pipeline, and with a special focus on current state-of-the-art methods. In general PET analysis using the FreeSurfer PET pipeline was able to reproduce the results estimated by gold standard procedures such as PVElab and SPM8. We were not able to obtain the exact same results as reported by McMahon et al., however this is likely to be caused by initial assumptions of volumes of interest and subsequent processing choices. The reported results seemed to be within an accepted range, indicating that FreeSurfer may be used as feasible tool in the analysis of PET data.
    MICCAI workshop on Computational Methods for Molecular Imaging 2015; 10/2015
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    • "Consistent with the preponderance of women with depression, 68% of the affected relatives were women (14 mothers, 10 sisters, 8 fathers, 2 brothers, and 0 children). Since short-allele carrier status of the 5-HTTLPR polymorphism in the promoter region of the SERT gene, SCL6A4, may modulate risk for developing depression (Caspi et al., 2003) and affect the 5-HT 4 receptor levels (Fisher et al., 2012), blood samples were drawn to determine the 5-HTTLPR status as previously described (Kalbitzer et al., 2010). "
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    ABSTRACT: The 5-HT4 receptor provides a novel potential target for antidepressant treatment. No studies exist to elucidate the 5-HT4 receptor's in vivo distribution in the depressed state or in populations that may display trait markers for major depression disorder (MDD). The aim of this study was to determine whether familial risk for MDD is associated with cerebral 5-HT4 receptor binding as measured with [(11)C]SB207145 brain PET imaging. Familial risk is the most potent risk factor of MDD. We studied 57 healthy individuals (age mean 36 yrs, range 20-86, 21 women) of which 26 had first degree relatives treated for MDD. We found that having a family history of MDD was associated with lower striatal 5-HT4 receptor binding (p=0.038 and in individuals below 40 years p=0.013). Further, we found evidence for a "risk-dose effect" on 5-HT4 receptor binding, since the number of first-degree relatives with a history of MDD binding correlated negatively with 5-HT4 receptor binding in both striatum (p=0.001) and limbic regions (p=0.012). Our data suggest that the 5-HT4 receptor is involved in the neurobiological mechanism underlying familial risk for depression and that lower striatal 5-HT4 receptor binding is associated with increasing risk for developing MDD. The finding is intriguing considering that the 5-HT4 receptor has been suggested to be an effective target for antidepressant treatment. © The Author 2014. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 10/2014; 18(1). DOI:10.1093/ijnp/pyu034 · 4.01 Impact Factor
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    • "Comparisons of 5-HTT binding in subjects with different 5-HTTLPR genotypes have been controversial since some studies have not been able to demonstrate any impact of genotype on 5-HTT function in vivo (Murthy et al., 2010; Parsey et al., 2006; Shioe et al., 2003) or post-mortem tissue (Mann et al., 2000). However, such lack of effects of 5- HTTLPR on altered 5-HTT binding can be explained by developmental or environmental rather than direct effects of 5-HTTLPR on adult serotonergic neurotransmission (Gaspar et al., 2003; Kalbitzer et al., 2010; Parsey et al., 2006; Willeit et al., 2008). Moreover, 5-HTTLPR genotypes seem to be affected by epigenetic mechanisms (Alasaari et al., 2012; Kinnally et al., 2010; van IJzendoorn et al., 2010), which could further explain inconclusive findings. "
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    ABSTRACT: A vast number of imaging studies have demonstrated the impact of serotonin (5-HT) and brain-derived neurotrophic factor (BDNF) on emotion and memory-related networks in the context of Major Depressive Disorder (MDD). Underlying molecular mechanisms that affect the functionality of these networks have been examined in detail in animals and corroborate imaging findings. The crucial role of 5-HT and BDNF signaling in the context of MDD is reflected in the etiologic models of MDD such as the monoamine or neuroplasticity hypothesis as well as in pharmacological models of antidepressant response. While antidepressant drug treatment has been primarily linked to the modulation of emotion-related networks, cognitive behavioral therapy has been implicated in a top-down control of limbic structures. Initially, a simple lack of monoamines or BDNF has been proposed as causal factor of MDD etiology. However, recent findings suggest a much more complex neurobiology emphasizing epistatic and epigenetic mechanisms responsible for structural and functional changes observed in emotion and memory-related brain regions of healthy subjects and MDD patients. In this review, which focuses on neuroimaging studies in the context of MDD, the authors will provide a comprehensive overview of these networks as well as on the specific role of 5-HT and BDNF in their development and function.
    04/2013; 32(1). DOI:10.3233/RNN-139005
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