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      Platelet Serotonin Transporter Function Predicts Default-Mode Network Activity

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          Abstract

          Background

          The serotonin transporter (5-HTT) is abundantly expressed in humans by the serotonin transporter gene SLC6A4 and removes serotonin (5-HT) from extracellular space. A blood-brain relationship between platelet and synaptosomal 5-HT reuptake has been suggested, but it is unknown today, if platelet 5-HT uptake can predict neural activation of human brain networks that are known to be under serotonergic influence.

          Methods

          A functional magnetic resonance study was performed in 48 healthy subjects and maximal 5-HT uptake velocity (V max) was assessed in blood platelets. We used a mixed-effects multilevel analysis technique (MEMA) to test for linear relationships between whole-brain, blood-oxygen-level dependent (BOLD) activity and platelet V max.

          Results

          The present study demonstrates that increases in platelet V max significantly predict default-mode network (DMN) suppression in healthy subjects independent of genetic variation within SLC6A4. Furthermore, functional connectivity analyses indicate that platelet V max is related to global DMN activation and not intrinsic DMN connectivity.

          Conclusion

          This study provides evidence that platelet V max predicts global DMN activation changes in healthy subjects. Given previous reports on platelet-synaptosomal V max coupling, results further suggest an important role of neuronal 5-HT reuptake in DMN regulation.

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          Most cited references63

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          Serotonin transporter genetic variation and the response of the human amygdala.

          Ahmad R Hariri, Venkata S. Mattay, Alessandro Tessitore … (2002)
          A functional polymorphism in the promoter region of the human serotonin transporter gene (SLC6A4) has been associated with several dimensions of neuroticism and psychopathology, especially anxiety traits, but the predictive value of this genotype against these complex behaviors has been inconsistent. Serotonin [5- hydroxytryptamine, (5-HT)] function influences normal fear as well as pathological anxiety, behaviors critically dependent on the amygdala in animal models and in clinical studies. We now report that individuals with one or two copies of the short allele of the serotonin transporter (5-HTT) promoter polymorphism, which has been associated with reduced 5-HTT expression and function and increased fear and anxiety-related behaviors, exhibit greater amygdala neuronal activity, as assessed by BOLD functional magnetic resonance imaging, in response to fearful stimuli compared with individuals homozygous for the long allele. These results demonstrate genetically driven variation in the response of brain regions underlying human emotional behavior and suggest that differential excitability of the amygdala to emotional stimuli may contribute to the increased fear and anxiety typically associated with the short SLC6A4 allele.
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            Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region.

            S Sabol, K-P Lesch, Russell D Hamer … (1996)
            Transporter-facilitated uptake of serotonin (5-hydroxytryptamine or 5-HT) has been implicated in anxiety in humans and animal models and is the site of action of widely used uptake-inhibiting antidepressant and antianxiety drugs. Human 5-HT transporter (5-HTT) gene transcription is modulated by a common polymorphism in its upstream regulatory region. The short variant of the polymorphism reduces the transcriptional efficiency of the 5-HTT gene promoter, resulting in decreased 5-HTT expression and 5-HT uptake in lymphoblasts. Association studies in two independent samples totaling 505 individuals revealed that the 5-HTT polymorphism accounts for 3 to 4 percent of total variation and 7 to 9 percent of inherited variance in anxiety-related personality traits in individuals as well as sibships.
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              Oxytocin modulates neural circuitry for social cognition and fear in humans.

              Peter Kirsch, Christine Esslinger, Qiang Chen … (2005)
              In non-human mammals, the neuropeptide oxytocin is a key mediator of complex emotional and social behaviors, including attachment, social recognition, and aggression. Oxytocin reduces anxiety and impacts on fear conditioning and extinction. Recently, oxytocin administration in humans was shown to increase trust, suggesting involvement of the amygdala, a central component of the neurocircuitry of fear and social cognition that has been linked to trust and highly expresses oxytocin receptors in many mammals. However, no human data on the effects of this peptide on brain function were available. Here, we show that human amygdala function is strongly modulated by oxytocin. We used functional magnetic resonance imaging to image amygdala activation by fear-inducing visual stimuli in 15 healthy males after double-blind crossover intranasal application of placebo or oxytocin. Compared with placebo, oxytocin potently reduced activation of the amygdala and reduced coupling of the amygdala to brainstem regions implicated in autonomic and behavioral manifestations of fear. Our results indicate a neural mechanism for the effects of oxytocin in social cognition in the human brain and provide a methodology and rationale for exploring therapeutic strategies in disorders in which abnormal amygdala function has been implicated, such as social phobia or autism.
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                Author and article information

                Contributors
                Andreas Androutsellis-Theotokis: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2014
                Publication date (Electronic): 25 March 2014
                Volume: 9
                Issue: 3
                Electronic Location Identifier: e92543
                Affiliations
                [1 ]Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria
                [2 ]Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
                [3 ]Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria
                [4 ]Center for Biomolecular Medicine and Pharmacology, Medical University of Vienna, Vienna, Austria
                [5 ]Department of Psychology, Dresden University of Technology, Dresden, Germany
                [6 ]Department of Statistics and Probability Theory, Vienna University of Technology, Vienna, Austria
                [7 ]Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany
                Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Germany
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: HE BB EM HHS LP MW MF AML. Performed the experiments: CS UR CHK TH LB GP ZU BH. Analyzed the data: UR CHK BMM KD HHS KK. Contributed reagents/materials/analysis tools: WH KK TP HH AML SK CW RL HE EM HHS LP. Wrote the paper: CS UR CHK BMM KD LB WH TP HH AML SK MF CW MW RL EH BB EM HHS LP.

                Article
                Publisher ID: PONE-D-13-00722
                DOI: 10.1371/journal.pone.0092543
                PMC ID: 3965432
                PubMed ID: 24667541
                SO-VID: 21cc42ef-55a7-4017-aad3-3120c4f87150
                Copyright statement: Copyright @ 2014
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 27 December 2012
                Date accepted : 25 February 2014
                Page count
                Pages: 10
                Funding
                This work was supported by the Special Research Project SFB-35 (Project No. F3514-B11, F3510-B11 and F3506-B11 to LP, MF and HHS, respectively) of the Austrian Science Fund (FWF) and the Institute for Study of Affective Neuroscience (ISAN) as well as by grants of the Austrian National Bank (OeNB P11903 to L. Pezawas and OeNB P13214 to R. Lanzenberger). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Neurochemistry
                Subject: Neurotransmitters
                Subject: Biogenic Amines
                Subject: Serotonin
                Subject: Neurochemicals
                Subject: Proteomics
                Subject: Evolutionary Biology
                Subject: Population Genetics
                Subject: Genetic Polymorphism
                Subject: Genetics
                Subject: Neuroscience
                Subject: Neuroimaging
                Subject: Systems Biology
                Subject: Medicine and Health Sciences
                Subject: Clinical Genetics
                Subject: Diagnostic Medicine
                Subject: Clinical Laboratory Sciences
                Subject: Mental Health and Psychiatry

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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