Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour. Philos Trans R Soc Lond B Biol Sci

Division of Molecular Psychiatry (MP), Laboratory of Translational Neuroscience (LTN), Department of Psychiatry, Psychosomatics, and Psychotherapy, University of Wuerzburg, , Fuechsleinstrasse 15, 97080 Wuerzburg, Germany.
Philosophical Transactions of The Royal Society B Biological Sciences (Impact Factor: 7.06). 09/2012; 367(1601):2426-43. DOI: 10.1098/rstb.2012.0039
Source: PubMed


Aggression, which comprises multi-faceted traits ranging from negative emotionality to antisocial behaviour, is influenced by an interaction of biological, psychological and social variables. Failure in social adjustment, aggressiveness and violence represent the most detrimental long-term outcome of neurodevelopmental disorders. With the exception of brain-specific tryptophan hydroxylase-2 (Tph2), which generates serotonin (5-HT) in raphe neurons, the contribution of gene variation to aggression-related behaviour in genetically modified mouse models has been previously appraised (Lesch 2005 Novartis Found Symp. 268, 111-140; Lesch & Merschdorf 2000 Behav. Sci. Law 18, 581-604). Genetic inactivation of Tph2 function in mice led to the identification of phenotypic changes, ranging from growth retardation and late-onset obesity, to enhanced conditioned fear response, increased aggression and depression-like behaviour. This spectrum of consequences, which are amplified by stress-related epigenetic interactions, are attributable to deficient brain 5-HT synthesis during development and adulthood. Human data relating altered TPH2 function to personality traits of negative emotionality and neurodevelopmental disorders characterized by deficits in cognitive control and emotion regulation are based on genetic association and are therefore not as robust as the experimental mouse results. Mouse models in conjunction with approaches focusing on TPH2 variants in humans provide unexpected views of 5-HT's role in brain development and in disorders related to negative emotionality, aggression and antisocial behaviour.

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Available from: Lise Gutknecht, Oct 05, 2015
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    • "In the brain serotonin serves as a neurotransmitter. It regulates multiple physiological aspects, including: behavior, learning , and appetite and glucose homeostasis, which have been extensively reviewed [6] [7] [8]. However, the brain-derived serotonin accounts only for around 5% of total body serotonin [5]. "
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    ABSTRACT: Metabolic homeostasis in the organism is assured both by the nervous system and by hormones. Among a plethora of hormones regulating metabolism, serotonin presents a number of unique features. Unlike classical hormones serotonin is produced in different anatomical locations. In brain it acts as a neurotransmitter and in the periphery it can act as a hormone, auto- and/or paracrine factor, or intracellular signaling molecule. Serotonin does not cross the blood-brain barrier; therefore the two major pools of this bioamine remain separated. Although 95% of serotonin is produced in the periphery, its functions have been ignored until recently. Here we review the impact of the peripheral serotonin on the regulation of function of the organs involved in glucose and lipid homeostasis. Copyright © 2015. Published by Elsevier B.V.
    FEBS letters 06/2015; 589(15). DOI:10.1016/j.febslet.2015.05.054 · 3.17 Impact Factor
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    • "Progress in Neuro-Psychopharmacology & Biological Psychiatry conditioned fear response, increased aggression and depression-like behavior have been identified (Lesch et al., 2013). In humans, a potentially functional single nucleotide polymorphism (SNP) G-703T (rs4570625) in the promoter region of the TPH2 gene has been described (Lin et al., 2007; Chen et al., 2008; but see Scheuch et al., 2007). "
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    ABSTRACT: The tryptophan hydroxylase-2 gene (TPH2) is coding for the key enzyme of serotonin (5-HT) synthesis in the brain and has been associated with a number of psychiatric conditions. A functional variation in the TPH2 gene (G-703T, rs4570625) has been found to affect anxiety-related personality; however, information is very limited regarding the five factor model (FFM) personality traits. We have examined the association of the TPH2 G-703T polymorphism with FFM personality traits, and the possible modulation by the functional variation in the serotonin transporter gene (5-HTTLPR) in a large longitudinal population representative sample. The FFM personality traits were assessed in both birth cohorts of the Estonian Children Personality Behaviour and Health Study at ages 15 (n = 742) and 18 ( n = 834). Significant association of the TPH2 genotype with Neuroticism and Conscientiousness was found at age 15, and with Extraversion and Conscientiousness at age 18. Participants with the T/T genotype scored significantly lower on Neuroticism and higher on Conscientiousness and Extraversion scales. In addition, a gene x gene interaction effect on Conscientiousness was revealed: the TPH2 genotype effect was evident only in the 5-HTTLPR S-allele carriers. These results provide further evidence on the possible role of genetic variations in 5-HT neurotransmission on development of personality traits, and suggest a functional interaction between two key proteins in the 5-HT-ergic system.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 03/2015; 57. DOI:10.1016/j.pnpbp.2014.10.005 · 3.69 Impact Factor
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    • "After the establishment of the central serotonergic system, a matured neurotransmitter phenotype manifested by the persistent expression of a myriad of transcription factors, enzymes, and synaptic proteins is maintained through mechanisms that are yet to be elucidated. Conceivably, an impaired maintenance of 5-HT neuronal phenotype may contribute to abnormal physiologic function and the etiology of psychiatric disorders such as depression, anxiety and schizophrenia [5-9]. "
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    ABSTRACT: Background: Despite the importance of 5-HT1A as a major target for the action of several anxiolytics/antidepressant drugs, little is known about its regulation in central serotonin (5-hydroxytryptamine, 5-HT) neurons. Results: We report that expression of 5-HT1A and the transcription factor Pet1 was impaired in the rostral raphe nuclei of mice lacking tryptophan hydroxylase 2 (Tph2) after birth. The downregulation of Pet1 was recapitulated in 5-Ht1a-/- mice. Using an explant culture system, we show that reduction of Pet1 and 5-HT1A was rescued in Tph2-/- brainstem by exogenous 5-HT. In contrast, 5-HT failed to rescue reduced expression of Pet1 in 5-Ht1a-/- brainstem explant culture. Conclusions: These results suggest a causal relationship between 5-HT1A and Pet1, and reveal a potential mechanism by which 5-HT1A-Pet1 autoregulatory loop is maintained by 5-HT in a spatiotemporal-specific manner during postnatal development. Our results are relevant to understanding the pathophysiology of certain psychiatric and developmental disorders.
    Molecular Brain 06/2014; 7(1):48. DOI:10.1186/1756-6606-7-48 · 4.90 Impact Factor
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