Roles for Serotonin in Neurodevelopment: More than just Neural Transmission

Pino, Giovanni Di; Moessner, Rainald; Lesch, Klaus‐Peter; Lauder, Jean M.; Persico, Antonio M.

doi:10.2174/1570159043359495

Cited by 42 publications

(27 citation statements)

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“…As 5-HT is known as an essential growth and regulatory factor that drives the development and maturation of its own cellular network and related neuronal systems (Pino et al, 2004;Oberlander, 2012), an excess of 5-HT may lead to impaired interneuron migration and abnormal development of the serotonergic system itself and its target regions (Pino et al, 2004;Oberlander, 2012). Here we suggest that elevated hypothalamic levels of 5-HT in recuperated animals in early life cause developmental and functional alterations that increase susceptibility to obesity later in life.…”

Section: Discussionmentioning

confidence: 74%

5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats

et al. 2016

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List of abbreviations5As the prevalence of obesity increases across the globe major efforts are directed at studying the mechanisms involved. Growing evidence suggests that susceptibility to obesity can be programmed by maternal and neonatal nutrition. In particular, individuals with low birth weight that undergo rapid postnatal growth are at higher risk of developing increased adiposity in later life. The molecular mechanisms mediating the interaction between early nutrition and obesity risk are, however, still largely unknown. Currently, there are no pharmacological therapies to prevent the increase in adiposity in individuals that underwent nutritional challenge in early life. Serotonin (5-HT) system is widely recognized as one of the key regulators of food intake and body weight. During fetal life serotonin also acts as a trophic factor that regulates brain development. As compounds targeting endogenous serotonin bioavailability have been among the most clinically effective treatments for obesity (e.g. d-fenfluramine), treatment targeting serotonin system may prevent the development of obesity in at risk individuals. Results:The study has shown that maternal protein restriction increased levels of serotonin in the blood of pregnant rat mums and in the placenta and the fetal brain. In adulthood the offspring had a reduced ability to sense serotonin, which was associated with a reduced hypothalamic expression of 5-HT2Creceptors -the primary serotonin receptor influencing appetite. As expected, reduced 5-HT2Creceptor expression was associated with impaired sensitivity to serotonin-mediated appetite suppression and hence could lead to increases in food intake. On the other hand offspring of low protein dams had a programmed increase in 5-HT2A receptors, which are positioned, just like 5-HT2C receptors, in the arcuate nucleus of the hypothalamus -a key area of the brain, involved in the control of food intake. Moreover, these animals were more sensitive to 5-HT2A receptor agonistinduced appetite suppression. Implications and future directions:This study identified a molecular mechanism that is involved in mediating the effects of suboptimal maternal diet on the regulation of food intake in the offspring. In addition, the authors showed that a treatment with 5-HT2A receptor agonist may potentially prevent the development of obesity in individuals that were exposed in utero to suboptimal nutrition and then underwent rapid postnatal growth. Non-hallucinogenic 5-HT2A receptor agonist should be used for such treatment. Combining the 5-HT2A receptor agonist with 5-HT2CR and 5-HT1BR agonists could potentially further increase the anorectic therapeutic effect. Disease Models & Mechanisms • DMM • Advance article AbstractThough obesity is a global epidemic, the physiological mechanisms involved are little understood.Recent advances reveal that susceptibility to obesity can be programmed by maternal and neonatal nutrition. Specifically, a maternal low protein diet during pregnancy causes decreased intrauterine growth, rapid...

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Section: Discussionmentioning

confidence: 74%

5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats

et al. 2016

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“…(b) Specification of raphe neurons lacking 5-HT synthesis Several in vitro studies showed a morphogenic effect of 5-HT on proliferation, differentiation, migration and survival of neural cells [80][81][82] 11,14). Conserved particularly is the expression of genes specifying a serotonergic phenotype in raphe neurons lacking 5-HT synthesis.…”

Section: Tph2 In Personality Traits Of Negative Emotionality and In Dmentioning

confidence: 99%

Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour

Lesch

Araragi

Waider

et al. 2012

Phil. Trans. R. Soc. B

128

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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.Keywords: tryptophan hydroxylase (TPH2); cognition; emotion; impulsivity; aggression; violence INTRODUCTIONNegative emotionality, aggression and antisociality are complex temperamental traits and social behaviours that arise out of multiple causes involving biological and psychological dynamisms and social forces, and different forms of emotional behaviour may each result from different biopsychosocial pathways. The societal implications of aggressiveness, which results in numerous facets of aggressive behaviour and ranges from the establishment of hierarchies and dominance to antisocial behaviour and delinquency, have been examined with preclinical and clinical frameworks.Developmentally inappropriate conduct, aggressiveness and failure in social adjustment represent the most detrimental and harmful long-term outcome of a wide spectrum of neurodevelopmental disorders characterized by deficits in cognitive control and emotion regulation.In both humans and animals, the term aggression comprises a variety of behaviours that are heterogeneous for clinical phenomenology and neurobiological features. While the impact of complex cultural variables on behaviour impedes simple extrapolation of animal phenotypes to human traits, clinical observation, experimental paradigms in the laboratory and cluster/ factor-analytic statistics have been used in attempts to subdivide aggression. On the basis of different approaches, hu...

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“…Serotonin is a phylogenetically ancient neurotransmitter widely distributed throughout key brain regions that influence cognition, emotion and learning [12,13]. From early fetal life, serotonin plays a primary role in modulating arousal, behavioral states, pain and responses to stress [14].…”

Section: Serotonin and Developmentmentioning

confidence: 99%

“…Serotonin has been implicated in the pathophysiology of numerous psychiatric and developmental disorders, and therefore it has been targeted in numerous pharmacological therapies [15,16]. Before serotonin becomes a neurotransmitter, it acts as a neurodevelopmental signal regulating cell growth and differentiation [13,15]. Thus, early alterations in serotonin may influence key developmental processes.…”

Section: Serotonin and Developmentmentioning

confidence: 99%

“…However, SSRIs cross the placenta and have been shown to accumulate in the fetal brain of sheep and rats [2,37]. In addition, perinatal exposures to SSRI and tricyclic antidepressants have a significant and long-term impact on the central serotonergic system [13,38,39,40]. These changes in serotonergic function likely influence many aspects of brain development and neural plasticity, both directly, such as through alterations in the serotonin transporter (SERT) [40], and indirectly, through alterations in other physiological systems such as the hypothalamic-pituitary-adrenal axis [41].…”

Section: Perinatal Exposure To Ssris and Neural Development: Preclinimentioning

confidence: 99%

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Perinatal Selective Serotonin Reuptake Inhibitor Exposure: Impact on Brain Development and Neural Plasticity

Pawluski¹

2011

Neuroendocrinology

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Selective serotonin reuptake inhibitor (SSRI) medications are the most common antidepressant treatment used during pregnancy and the postpartum period. Up to 10% of pregnant women are prescribed SSRIs. Serotonin plays an integral part in neurodevelopment, and questions have been raised about the placental transfer of SSRIs and the effects of preventing reuptake of presynaptic serotonin on fetal neurodevelopment. Preclinical data is beginning to document a role of early exposure to SSRIs in long-term developmental outcomes related to a number of brain regions, such as the hippocampus, cortex and cerebellum. To date, the majority of preclinical work has investigated the developmental effects of SSRIs in the offspring of healthy mothers; however, more research is needed on the effects of these medications in the face of maternal adversity. This minireview will highlight emerging evidence from clinical and preclinical studies investigating the impact of perinatal SSRI exposure on brain development and neural plasticity.

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Roles for Serotonin in Neurodevelopment: More than just Neural Transmission

Cited by 42 publications

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5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats

5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats

Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour

Perinatal Selective Serotonin Reuptake Inhibitor Exposure: Impact on Brain Development and Neural Plasticity

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