title: Impact of Maternal Serotonin Transporter Genotype on Placental Serotonin, Fetal Forebrain Serotonin, and Neurodevelopment.
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.
authors.affiliation: Graduate Program in Neuroscience, Vanderbilt University, Nashville, TN, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Muller
authors.affiliation: Department of Psychiatry, Columbia University Medical School, New York, NY, USA.
authors.forename: Allison Mj
authors.initials: AM
authors.lastname: Anacker
authors.affiliation: Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Tiffany D
authors.initials: TD
authors.lastname: Rogers
authors.affiliation: Department of Cell and Neurobiology and Zilkha Neurogenetic Institute, University of Southern California School of Medicine, Los Angeles, CA, USA.
authors.forename: Nick
authors.initials: N
authors.lastname: Goeden
authors.affiliation: Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Keller
authors.affiliation: Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: C Gunnar
authors.initials: CG
authors.lastname: Forsberg
authors.affiliation: Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Travis M
authors.initials: TM
authors.lastname: Kerr
authors.affiliation: Department of Psychiatry, Columbia University Medical School, New York, NY, USA.
authors.forename: Carly LA
authors.initials: C
authors.lastname: Wender
authors.affiliation: Child Study Center, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: George M
authors.initials: GM
authors.lastname: Anderson
authors.affiliation: Department of Biomedical Sciences, Florida State University, Tallahassee, FL, USA.
authors.forename: Gregg D
authors.initials: GD
authors.lastname: Stanwood
authors.affiliation: Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA.|Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Randy D
authors.initials: RD
authors.lastname: Blakely
authors.affiliation: Department of Cell and Neurobiology and Zilkha Neurogenetic Institute, University of Southern California School of Medicine, Los Angeles, CA, USA.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bonnin
authors.affiliation: Department of Psychiatry, Columbia University Medical School, New York, NY, USA.|New York State Psychiatric Institute, New York, NY, USA.|Center for Autism and the Developing Brain, New York Presbyterian Hospital, New York, NY, USA.|Sackler Institute for Developmental Psychobiology, Columbia University, New York, NY, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Veenstra-VanderWeele
mesh_terms: D000818:Animals; D005260:Female; D005838:Genotype; D008431:Maternal-Fetal Exchange; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D016548:Prosencephalon / Q000196:embryology* / Q000378:metabolism*; D012249:Rhombencephalon / Q000378:metabolism; D012701:Serotonin / Q000096:biosynthesis*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D013788:Thalamus / Q000196:embryology / Q000378:metabolism
chemical_list: D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D012701:Serotonin