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
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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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    • "Of the identified GDF8 variations in humans, the Lys(K)153Arg(R) polymorphism in exon 2 (rs1805086; 2379 A>G replacement) of the myostatin (MSTN) gene is a candidate to influence skeletal muscle phenotypes (Ferrell et al. 1999; Kostek et al. 2009; Santiago et al. 2011). As for neurotransmission the serotonin transporter gene SLC6A4 (also called SERT or 5HTT), the dopamine transporter gene SLC6A3 (commonly referred as DAT), and the monoamine oxidase A gene (MAOA) have been considered as directly involved in the management of aggressiveness, anxiety and fear (Deckert et al. 1999; Melke et al. 2001; Gerra et al. 2005; Weintraub et al. 2005; Lesch et al. 2012; Pavlov et al. 2012) and therefore potentially involved in emotional management of psychological insights. In this work we assessed the contribution given by 4 different genes involved respectively in muscles development and behavioral insights defining possible action of Nature and Nurture to athletic performances and success. "
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    ABSTRACT: Elite athletes are those who represent their sport at such major competition as the Olympic Games or World contests. The most outstanding athletes appear to emerge as a result of endogenous biologic characteristics interacting with exogenous influences of the environment, often described as a 'Nature and Nurture' struggle. In this work, we assessed the contribution given by 4 genes involved in muscles development (MSTN) and behavioural insights (5HTT, DAT and MAOA) to athletic performances. As for neurotransmission, 5HTT, DAT and MAOA genes have been considered as directly involved in the management of aggressiveness and anxiety. Genotypes and allelic frequencies of 5HTTLPR, MAOA-u VNTR, DAT VNTR and MSTN K153R were determined in 50 elite athletes and compared with 100 control athletes. In this work we found a significant correlation between the dopamine transporter genotype 9/9 and allele 9 and elite sport performances. On the contrary, no association was found between muscle development regulation or serotonin pathway and elite performances. Our data, for the first time, suggest a strong role of dopamine neurotransmitter in determining sport success, highlighting the role of emotional control and psycological management to reach high-level performances.
    Journal of Biosciences 09/2015; 40(3):531-7. DOI:10.1007/s12038-015-9542-4 · 2.06 Impact Factor
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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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    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.
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