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A transient placental source of serotonin for the fetal forebrain

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      Abstract

      Serotonin (5-hydroxytryptamine; 5-HT) is thought to regulate neurodevelopmental processes through maternal-fetal interactions that have long-term mental health implications. Dogma states that beyond fetal 5-HT neurons, there are significant maternal contributions to fetal 5-HT during pregnancy1,2, but this has not been tested empirically. To examine putative central and peripheral sources of embryonic brain 5-HT, we used the Pet-1−/− mice in which most dorsal raphe (DR) neurons lack 5-HT3. Measures of 5-HT revealed previously unknown differences in accumulation between the fore- and hindbrain during early and late fetal stages, through an exogenous source of 5-HT. We show that this source is not of maternal origin. Using additional genetic strategies, a new technology for studying placental biology ex vivo, and direct manipulation of placental neosynthesis, we investigated the nature of this exogenous source and uncovered a placental 5-HT synthetic pathway from a maternal tryptophan precursor, in both mice and humans. This study reveals a new, direct role for placental metabolic pathways in modulating fetal brain development and implicates novel maternal-placental-fetal interactions that could underlie the pronounced impact of 5-HT on long-lasting mental health outcomes.

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      Most cited references 30

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      Prenatal infection and schizophrenia: a review of epidemiologic and translational studies.

      An emerging literature from epidemiologic, clinical, and preclinical investigations has provided evidence that gestational exposure to infection contributes to the etiology of schizophrenia. In recent years, these studies have moved from ecologic designs, which ascertain infection based on epidemics in populations, to investigations that have capitalized on reliable biomarkers in individual pregnancies. These studies have documented specific candidate infections that appear to be associated with an elevated risk of schizophrenia. Animal models of maternal immune activation inspired by this work have revealed intriguing findings indicating behavioral, neurochemical, and neurophysiologic abnormalities consistent with observations in schizophrenia. In parallel studies in humans and animals, investigators are working to uncover the cellular and molecular mechanisms by which in utero exposure to infection contributes to schizophrenia risk. In this review, the authors discuss and critically evaluate the epidemiologic literature on in utero exposure to infection and schizophrenia, summarize emerging animal models of maternal immune activation, and discuss putative unique and common mechanisms by which in utero exposure to infection alters neurodevelopment, potentially increasing susceptibility to schizophrenia. The promise of this work for facilitating the identification of susceptibility loci in genetic studies of schizophrenia is illustrated by examples of interaction between in utero exposure to infection and genetic variants. The authors then elaborate on possible implications of this work, including the use of preventive measures for reducing the incidence of schizophrenia. Finally, they discuss new approaches aimed at addressing current challenges in this area of research.
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        The developmental role of serotonin: news from mouse molecular genetics.

        New genetic models that target the serotonin system show that transient alterations in serotonin homeostasis cause permanent changes to adult behaviour and modify the fine wiring of brain connections. These findings have revived a long-standing interest in the developmental role of serotonin. Molecular genetic approaches are now showing us that different serotonin receptors, acting at different developmental stages, modulate different developmental processes such as neurogenesis, apoptosis, axon branching and dendritogenesis. Our understanding of the specification of the serotonergic phenotype is improving. In addition, studies have revealed that serotonergic traits are dissociable, as there are populations of neurons that contain serotonin but do not synthesize it.
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          Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice.

          Reduced serotonin transporter (5-HTT) expression is associated with abnormal affective and anxiety-like symptoms in humans and rodents, but the mechanism of this effect is unknown. Transient inhibition of 5-HTT during early development with fluoxetine, a commonly used serotonin selective reuptake inhibitor, produced abnormal emotional behaviors in adult mice. This effect mimicked the behavioral phenotype of mice genetically deficient in 5-HTT expression. These findings indicate a critical role of serotonin in the maturation of brain systems that modulate emotional function in the adult and suggest a developmental mechanism to explain how low-expressing 5-HTT promoter alleles increase vulnerability to psychiatric disorders.
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            Author and article information

            Affiliations
            [1 ] Zilkha Neurogenetic Institute, Keck School of Medicine of USC, Los Angeles, CA, 90089, USA
            [2 ] Department of Cell & Neurobiology, Keck School of Medicine of USC, Los Angeles, CA, 90089, USA
            [3 ] Department of Pharmacology & Pharmaceutical Sciences, USC School of Pharmacy, Los Angeles, CA 90089, USA
            [4 ] Departments of OB/GYN & Preventive Medicine, Keck School of Medicine of USC, Los Angeles, CA 90089, USA
            [5 ] Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37221, USA
            [6 ] Center for Molecular Neuroscience, Vanderbilt University Medical Center, Nashville, TN 37221, USA
            [7 ] Department of Neuroscience, Case Western Reserve University School of Medicine, Cleveland, OH, USA
            Author notes
            Correspondence and requests for materials should be addressed to A.B. ( bonnin@ 123456usc.edu ) or P.L. ( plevitt@ 123456usc.edu )
            Journal
            0410462
            6011
            Nature
            Nature
            Nature
            0028-0836
            1476-4687
            30 March 2011
            21 April 2011
            21 October 2011
            : 472
            : 7343
            : 347-350
            3084180
            21512572
            10.1038/nature09972
            nihpa276130

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            Funding
            Funded by: National Institute of Child Health & Human Development : NICHD
            Award ID: R21 HD065287-02 || HD
            Funded by: National Institute of Child Health & Human Development : NICHD
            Award ID: R21 HD065287-01 || HD
            Funded by: National Institute of Mental Health : NIMH
            Award ID: P50 MH078028-05 || MH
            Funded by: National Institute of Mental Health : NIMH
            Award ID: P50 MH078028-04 || MH
            Funded by: National Institute of Mental Health : NIMH
            Award ID: P50 MH078028-03 || MH
            Funded by: National Institute of Mental Health : NIMH
            Award ID: P50 MH078028-02 || MH
            Funded by: National Institute of Mental Health : NIMH
            Award ID: P50 MH078028-01A1 || MH
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