Abstract
Biomarker, neuroimaging, and genetic findings implicate the serotonin transporter (SERT) in autism spectrum disorder (ASD). Previously, we found that adult male mice expressing the autism-associated SERT Ala56 variant have altered central serotonin (5-HT) system function, as well as elevated peripheral blood 5-HT levels. Early in gestation, before midbrain 5-HT projections have reached the cortex, peripheral sources supply 5-HT to the forebrain, suggesting that altered maternal or placenta 5-HT system function could impact the developing embryo. We therefore used different combinations of maternal and embryo SERT Ala56 genotypes to examine effects on blood, placenta and embryo serotonin levels and neurodevelopment at embryonic day E14.5, when peripheral sources of 5-HT predominate, and E18.5, when midbrain 5-HT projections have reached the forebrain. Maternal SERT Ala56 genotype was associated with decreased placenta and embryonic forebrain 5-HT levels at E14.5. Low 5-HT in the placenta persisted, but forebrain levels normalized by E18.5. Maternal SERT Ala56 genotype effects on forebrain 5-HT levels were accompanied by a broadening of 5-HT-sensitive thalamocortical axon projections. In contrast, no effect of embryo genotype was seen in concepti from heterozygous dams. Blood 5-HT levels were dynamic across pregnancy and were increased in SERT Ala56 dams at E14.5. Placenta RNA sequencing data at E14.5 indicated substantial impact of maternal SERT Ala56 genotype, with alterations in immune and metabolic-related pathways. Collectively, these findings indicate that maternal SERT function impacts offspring placental 5-HT levels, forebrain 5-HT levels, and neurodevelopment.
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References
Amireault P, Sibon D, Cote F (2013). Life without peripheral serotonin: insights from tryptophan hydroxylase 1 knockout mice reveal the existence of paracrine/autocrine serotonergic networks. ACS Chem Neurosci 4: 64–71.
Anders S, McCarthy DJ, Chen Y, Okoniewski M, Smyth GK, Huber W et al (2013). Count-based differential expression analysis of RNA sequencing data using R and Bioconductor. Nat Protoc 8: 1765–1786.
Anders S, Pyl PT, Huber W (2014). HTSeq-a Python framework to work with high-throughput sequencing data. Bioinformatics 31: 166–169.
Anderson GM, Feibel FC, Cohen DJ (1987). Determination of serotonin in whole blood, platelet-rich plasma, platelet-poor plasma and plasma ultrafiltrate. Life Sci 40: 1063–1070.
Anderson GM, Jacobs-Stannard A, Chawarska K, Volkmar FR, Kliman HJ (2007). Placental trophoblast inclusions in autism spectrum disorder. Biol Psychiatry 61: 487–491.
Balsells M, Garcia-Patterson A, Gich I, Corcoy R (2012). Major congenital malformations in women with gestational diabetes mellitus: a systematic review and meta-analysis. Diabetes Metab Res Rev 28: 252–257.
Bonnin A, Goeden N, Chen K, Wilson ML, King J, Shih JC et al (2011). A transient placental source of serotonin for the fetal forebrain. Nature 472: 347–350.
Bonnin A, Peng W, Hewlett W, Levitt P (2006). Expression mapping of 5-HT1 serotonin receptor subtypes during fetal and early postnatal mouse forebrain development. Neuroscience 141: 781–794.
Bonnin A, Torii M, Wang L, Rakic P, Levitt P (2007). Serotonin modulates the response of embryonic thalamocortical axons to netrin-1. Nature Neurosci 10: 588–597.
Bronson SL, Bale TL (2014). Prenatal stress-induced increases in placental inflammation and offspring hyperactivity are male-specific and ameliorated by maternal antiinflammatory treatment. Endocrinology 155: 2635–2646.
Cases O, Vitalis T, Seif I, De Maeyer E, Sotelo C, Gaspar P (1996). Lack of barrels in the somatosensory cortex of monoamine oxidase A-deficient mice: role of a serotonin excess during the critical period. Neuron 16: 297–307.
Chen X, Ye R, Gargus JJ, Blakely RD, Dobrenis K, Sze JY (2015). Disruption of transient serotonin accumulation by non-serotonin-producing neurons impairs cortical map development. Cell Rep 10: 346–358.
Cote F, Fligny C, Bayard E, Launay JM, Gershon MD, Mallet J et al (2007). Maternal serotonin is crucial for murine embryonic development. Proc Natl Acad Sci USA 104: 329–334.
Cray C (2012). Acute phase proteins in animals. Prog Mol Biol Transl Sci 105: 113–150.
Devlin B, Cook EH Jr, Coon H, Dawson G, Grigorenko EL, McMahon W et al (2005). Autism and the serotonin transporter: the long and short of it. Mol Psychiatry 10: 1110–1116.
Gabriele S, Sacco R, Persico AM (2014). Blood serotonin levels in autism spectrum disorder: a systematic review and meta-analysis. Eur Neuropsychopharmacol 24: 919–929.
Gaspar P, Cases O, Maroteaux L (2003). The developmental role of serotonin: news from mouse molecular genetics. Nat Rev Neurosci 4: 1002–1012.
Gleason G, Liu B, Bruening S, Zupan B, Auerbach A, Mark W et al (2010). The serotonin1A receptor gene as a genetic and prenatal maternal environmental factor in anxiety. Proc Natl Acad Sci USA 107: 7592–7597.
Goeden N, Bonnin A (2013). Ex vivo perfusion of mid-to-late-gestation mouse placenta for maternal-fetal interaction studies during pregnancy. Nat Protoc 8: 66–74.
Goeden N, Velasquez J, Arnold KA, Chan Y, Lund BT, Anderson GM et al (2016). Maternal inflammation disrupts fetal neurodevelopment via increased placental output of serotonin to the fetal brain. J Neurosci 36: 6041–6049.
Hong C, Tontonoz P (2014). Liver X receptors in lipid metabolism: opportunities for drug discovery. Nat Rev Drug Discov 13: 433–444.
Hsiao EY, Patterson PH (2011). Activation of the maternal immune system induces endocrine changes in the placenta via IL-6. Brain Behav Immun 25: 604–615.
Hsiao EY, Patterson PH (2012). Placental regulation of maternal-fetal interactions and brain development. Dev Neurobiol 72: 1317–1326.
Janowski BA, Willy PJ, Devi TR, Falck JR, Mangelsdorf DJ (1996). An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature 383: 728–731.
Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg SL (2013). TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol 14: R36.
Kistner-Griffin E, Brune CW, Davis LK, Sutcliffe JS, Cox NJ, Cook EH Jr (2011). Parent-of-origin effects of the serotonin transporter gene associated with autism. Am J Med Genet B Neuropsychiatr Genet 156: 139–144.
Kuipers F, Bloks VW, Groen AK (2014). Beyond intestinal soap—bile acids in metabolic control. Nat Rev Endocrinol 10: 488–498.
Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N et al (2009a). The sequence alignment/map format and SAMtools. Bioinformatics 25: 2078–2079.
Li M, Huang SJ (2009b). Innate immunity, coagulation and placenta-related adverse pregnancy outcomes. Thromb Res 124: 656–662.
Li Y, Hadden C, Singh P, Mercado CP, Murphy P, Dajani NK et al (2014). GDM-associated insulin deficiency hinders the dissociation of SERT from ERp44 and down-regulates placental 5-HT uptake. Proc Natl Acad Sci USA 111: E5697–E5705.
Malkova NV, Yu CZ, Hsiao EY, Moore MJ, Patterson PH (2012). Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain Behav Immun 26: 607–616.
McCarthy DJ, Chen Y, Smyth GK (2012). Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation. Nucleic Acids Res 40: 4288–4297.
Muller CL, Anacker AM, Veenstra-VanderWeele J (2015). The serotonin system in autism spectrum disorder: From biomarker to animal models. Neuroscience 321: 24–41.
Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA et al (1999). Bile acids: natural ligands for an orphan nuclear receptor. Science 284: 1365–1368.
Prasad HC, Steiner JA, Sutcliffe JS, Blakely RD (2009). Enhanced activity of human serotonin transporter variants associated with autism. Philos Trans Roy Soc Lond B Biol Sci 364: 163–173.
Radaelli T, Varastehpour A, Catalano P, Hauguel-de Mouzon S (2003). Gestational diabetes induces placental genes for chronic stress and inflammatory pathways. Diabetes 52: 2951–2958.
Robson JM, Senior JB (1964). The 5-hydroxytryptamine content of the placenta and foetus during pregnancy in mice. Br J Pharmacol Chemother 22: 380–391.
Sakurai T, Reichert J, Hoffman EJ, Cai G, Jones HB, Faham M et al (2008). A large-scale screen for coding variants in SERT/SLC6A4 in autism spectrum disorders. Autism Res 1: 251–257.
Schauder KB, Muller CL, Veenstra-VanderWeele J, Cascio CJ (2015). Genetic variation in serotonin transporter modulates tactile hyperresponsiveness in ASD. Res Autism Spectr Disord 10: 93–100.
Schroeder A, Mueller O, Stocker S, Salowsky R, Leiber M, Gassmann M et al (2006). The RIN: an RNA integrity number for assigning integrity values to RNA measurements. BMC Mol Biol 7: 3.
Sutcliffe JS, Delahanty RJ, Prasad HC, McCauley JL, Han Q, Jiang L et al (2005). Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors. Am J Hum Genet 77: 265–279.
Toth M (2014). Mechanisms of non-genetic inheritance and psychiatric disorders. Neuropsychopharmacology 40: 129–140.
Tsang KM, Croen LA, Torres AR, Kharrazi M, Delorenze GN, Windham GC et al (2013). A genome-wide survey of transgenerational genetic effects in autism. PLoS One 8: e76978.
Veenstra-VanderWeele J, Jessen TN, Thompson BJ, Carter M, Prasad HC, Steiner JA et al (2009). Modeling rare gene variation to gain insight into the oldest biomarker in autism: construction of the serotonin transporter Gly56Ala knock-in mouse. J Neurodev Disord 1: 158–171.
Veenstra-VanderWeele J, Muller CL, Iwamoto H, Sauer JE, Owens WA, Shah CR et al (2012). Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior. Proc Natl Acad Sci USA 109: 5469–5474.
Verhaagh S, Barlow DP, Zwart R (2001). The extraneuronal monoamine transporter Slc22a3/Orct3 co-localizes with the Maoa metabolizing enzyme in mouse placenta. Mech Dev 100: 127–130.
Walker CK, Anderson KW, Milano KM, Ye S, Tancredi DJ, Pessah IN et al (2013). Trophoblast inclusions are significantly increased in the placentas of children in families at risk for autism. Biol Psychiatry 74: 204–211.
Walker CK, Krakowiak P, Baker A, Hansen RL, Ozonoff S, Hertz-Picciotto I (2015). Preeclampsia, placental insufficiency, and autism spectrum disorder or developmental delay. JAMA Pediatr 169: 154–162.
Weiss LA, Abney M, Cook EH Jr, Ober C (2005). Sex-specific genetic architecture of whole blood serotonin levels. Am J Hum Genet 76: 33–41.
Wu HH, Choi S, Levitt P (2016). Differential patterning of genes involved in serotonin metabolism and transport in extra-embryonic tissues of the mouse. Placenta 42: 74–83.
Yonan AL, Alarcon M, Cheng R, Magnusson PK, Spence SJ, Palmer AA et al (2003). A genomewide screen of 345 families for autism-susceptibility loci. Am J Hum Genet 73: 886–897.
Yuan H, Dougherty JD (2014). Investigation of maternal genotype effects in autism by genome-wide association. Autism Res 7: 245–253.
Acknowledgements
The authors would like to thank Bing Zhang, PhD, and Jing Wang, PhD, for biostatistics and bioinformatics assistance.
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Muller, C., Anacker, A., Rogers, T. et al. Impact of Maternal Serotonin Transporter Genotype on Placental Serotonin, Fetal Forebrain Serotonin, and Neurodevelopment. Neuropsychopharmacol 42, 427–436 (2017). https://doi.org/10.1038/npp.2016.166
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DOI: https://doi.org/10.1038/npp.2016.166
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