{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T06:21:40Z","timestamp":1786429300261,"version":"build-2736575974"},"reference-count":116,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,3]],"date-time":"2021-06-03T00:00:00Z","timestamp":1622678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:p>Altered structure, expression, and regulation of the presynaptic serotonin (5-HT) transporter (SERT) have been associated with multiple neurobehavioral disorders, including mood disorders, obsessive-compulsive disorder (OCD), and autism spectrum disorder (ASD). Opportunities to investigate mechanistic links supporting these associations were spurred with the identification of multiple, rare human SERT coding variants in a study that established a male-specific linkage of ASD to a linkage marker on chromosome 17 which encompassed the location of the SERT gene (<jats:italic>SLC6A4<\/jats:italic>). We have explored the most common of these variants, SERT Ala56, <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. Results support a tonic elevation of 5-HT transport activity in transfected cells and human lymphoblasts by the variant <jats:italic>in vitro<\/jats:italic> that leads to an increased 5-HT clearance rate <jats:italic>in vivo<\/jats:italic> when studied in the SERT Ala56 mouse model, along with altered sensitivity to SERT regulatory signaling pathways. Importantly, hyperserotonemia, or an elevated whole blood 5-HT, level, was found in SERT Ala56 mice, reproducing a well-replicated trait observed in a significant fraction of ASD subjects. Additionally, we found multiple biochemical, physiological, and behavioral alterations in the SERT Ala56 mice that can be analogized to those observed in ASD and its medical comorbidities. The similarity of the functional impact of the SERT Ala56 variant to the consequences of p38\u03b1 MAPK activation, ascribed to the induction of a biased conformation of the transporter toward an outward-facing conformation, has resulted in successful efforts to restore normal behavioral and bowel function <jats:italic>via<\/jats:italic> pharmacological and genetic p38\u03b1 MAPK targeting. Moreover, the ability of the inflammatory cytokine IL-1\u03b2 to enhance SERT activity <jats:italic>via<\/jats:italic> a p38\u03b1 MAPK-dependent pathway suggests that the SERT Ala56 conformation mimics that of a chronic inflammatory state, supporting findings in ASD of elevated inflammatory cytokine levels. In this report, we review studies of the SERT Ala56 variant, discussing opportunities for continued insight into how chronically altered synaptic 5-HT homeostasis can drive reversible, functional perturbations in 5-HT sensitive pathways in the brain and periphery, and how targeting the SERT regulome, particularly through activating pathways such as those involving IL-1\u03b2\/p38\u03b1 MAPK, may be of benefit for neurobehavioral disorders, including ASD.<\/jats:p>","DOI":"10.3389\/fncel.2021.677563","type":"journal-article","created":{"date-parts":[[2021,6,3]],"date-time":"2021-06-03T23:30:10Z","timestamp":1622763010000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Rare Opportunities for Insights Into Serotonergic Contributions to Brain and Bowel Disorders: Studies of the SERT Ala56 Mouse"],"prefix":"10.3389","volume":"15","author":[{"given":"Samantha E.","family":"Stilley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randy D.","family":"Blakely","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,6,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1394","DOI":"10.1093\/cercor\/bhl051","article-title":"Altered neocortical cell density and layer thickness in serotonin transporter knockout mice: a quantitation study","volume":"17","author":"Altamura","year":"2007","journal-title":"Cereb. cortex"},{"key":"B2","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1002\/(SICI)1096-8628(19960726)67:4<409::AID-AJMG16>3.0.CO;2-N","article-title":"Intact coding region of the serotonin transporter gene in obsessive\u2013compulsive disorder","volume":"67","author":"Altemus","year":"1996","journal-title":"Am. J. Med. Genet."},{"key":"B3","volume-title":"Diagnostic And Statistical Manual Of Mental Disorders-Text Revision (DSM-IV-TR; 4th edition).","year":"2000"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1016\/0024-3205(87)90568-6","article-title":"Determination of serotonin in whole blood, platelet-rich plasma, platelet-poor plasma and plasma ultrafiltrate","volume":"40","author":"Anderson","year":"1987","journal-title":"Life Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1021\/cn300186b","article-title":"A dialogue between the immune system and brain, spoken in the language of serotonin","volume":"4","author":"Baganz","year":"2013","journal-title":"ACS Chem. Neurosci."},{"key":"B5","doi-asserted-by":"publisher","first-page":"e671","DOI":"10.1038\/tp.2015.168","article-title":"A requirement of serotonergic p38\u03b1 mitogen-activated protein kinase for peripheral immune system activation of CNS serotonin uptake and serotonin-linked behaviors","volume":"5","author":"Baganz","year":"2015","journal-title":"Transl. Psychiatry"},{"key":"B8","doi-asserted-by":"publisher","first-page":"7571","DOI":"10.1523\/JNEUROSCI.20-20-07571.2000","article-title":"Cocaine and antidepressant-sensitive biogenic amine transporters exist in regulated complexes with protein phosphatase 2A","volume":"20","author":"Bauman","year":"2000","journal-title":"J. Neurosci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"888","DOI":"10.1124\/pr.115.012260","article-title":"Kinase-dependent regulation of monoamine neurotransmitter transporters","volume":"68","author":"Bermingham","year":"2016","journal-title":"Pharmacol. Rev."},{"key":"B10","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1038\/sj\/mp\/4000923","article-title":"Serotonin transporter gene polymorphisms and hyperserotonemia in autistic disorder","volume":"7","author":"Betancur","year":"2002","journal-title":"Mol. Psychiatry"},{"key":"B11","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1038\/354066a0","article-title":"Cloning and expression of a functional serotonin transporter from rat brain","volume":"354","author":"Blakely","year":"1991","journal-title":"Nature"},{"key":"B12","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1152\/physiol.00013.2005","article-title":"Biogenic amine neurotransmitter transporters: just when you thought you knew them","volume":"20","author":"Blakely","year":"2005","journal-title":"Physiology"},{"key":"B13","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1038\/nature09972","article-title":"A transient placental source of serotonin for the fetal forebrain","volume":"472","author":"Bonnin","year":"2011","journal-title":"Nature"},{"key":"B14","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1038\/nn1896","article-title":"Serotonin modulates the response of embryonic thalamocortical axons to netrin-1","volume":"10","author":"Bonnin","year":"2007","journal-title":"Nat. Neurosci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1356","DOI":"10.1046\/j.1471-4159.1997.69041356.x","article-title":"Alternative splicing of the human serotonin transporter gene","volume":"69","author":"Bradley","year":"1997","journal-title":"J. Neurochem."},{"key":"B16","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/2040-2392-4-28","article-title":"Rare coding variants of the adenosine A3 receptor are increased in autism: on the trail of the serotonin transporter regulome","volume":"4","author":"Campbell","year":"2013","journal-title":"Mol. Autism"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1544","DOI":"10.1172\/JCI33374","article-title":"Interactions between integrin alphaIIbbeta3 and the serotonin transporter regulate serotonin transport and platelet aggregation in mice and humans","volume":"118","author":"Carneiro","year":"2008","journal-title":"J. Clin. Invest."},{"key":"B18","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/s0169-328x(96)00172-6","article-title":"Cloning and expression of the mouse serotonin transporter","volume":"43","author":"Chang","year":"1996","journal-title":"Mol. Brain Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"8919","DOI":"10.1523\/JNEUROSCI.0048-12.2012","article-title":"Single molecule analysis of serotonin transporter regulation using antagonist-conjugated quantum dots reveals restricted, p38 MAPK-dependent mobilization underlying uptake activation","volume":"32","author":"Chang","year":"2012","journal-title":"J. Neurosci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1016\/j.celrep.2014.12.033","article-title":"Disruption of transient serotonin accumulation by non-serotonin-producing neurons impairs cortical map development","volume":"10","author":"Chen","year":"2015","journal-title":"Cell Rep."},{"key":"B21","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1002\/1531-8249(199903)45:3<287::aid-ana3>3.0.co;2-9","article-title":"Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children","volume":"45","author":"Chugani","year":"1999","journal-title":"Ann. Neurol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1038\/s41594-018-0026-8","article-title":"Structural basis for recognition of diverse antidepressants by the human serotonin transporter","volume":"25","author":"Coleman","year":"2018","journal-title":"Nat. Struct. Mol. Biol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1038\/nature17629","article-title":"X-ray structures and mechanism of the human serotonin transporter","volume":"532","author":"Coleman","year":"2016","journal-title":"Nature"},{"key":"B24","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/s41586-019-1135-1","article-title":"Serotonin transporter-ibogaine complexes illuminate mechanisms of inhibition and transport","volume":"569","author":"Coleman","year":"2019","journal-title":"Nature"},{"key":"B25","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1097\/00008480-199608000-00008","article-title":"The serotonin system in autism","volume":"8","author":"Cook","year":"1996","journal-title":"Curr. Opin. Pediatr."},{"key":"B26","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1097\/00004583-199207000-00024","article-title":"Fluoxetine treatment of children and adults with autistic disorder and mental retardation","volume":"31","author":"Cook","year":"1992","journal-title":"J. Am. Acad. Child Adolesc. Psychiatry"},{"key":"B27","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1038\/sj.mp.4001409","article-title":"Variants of the serotonin transporter gene (SLC6A4) significantly contribute to hyperserotonemia in autism","volume":"9","author":"Coutinho","year":"2004","journal-title":"Mol. Psychiatry"},{"key":"B203","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1523\/JNEUROSCI.12-03-01101.1992","article-title":"In situ histochemical localization of type I interleukin-1 receptor messenger RNA in the central nervous system, pituitary, and adrenal gland of the mouse","volume":"12","author":"Cunningham","year":"1992","journal-title":"J. Neurosci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1002\/(SICI)1096-8628(19961122)67:6<541::AID-AJMG5>3.0.CO;2-K","article-title":"Systematic screening for mutations in the coding region of the human serotonin transporter (5-HTT) gene using PCR and DGGE","volume":"67","author":"Di Bella","year":"1996","journal-title":"Am. J. Med. Genet."},{"key":"B29","doi-asserted-by":"publisher","first-page":"11271","DOI":"10.1523\/JNEUROSCI.1482-17.2017","article-title":"The gain-of-function integrin \u03b23 pro33 variant alters the serotonin system in the mouse brain","volume":"37","author":"Dohn","year":"2017","journal-title":"J. Neurosci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"800","DOI":"10.1038\/169800b0","article-title":"Identification of enteramine, the specific hormone of the enterochromaffin cell system, as 5-hydroxytryptamine","volume":"169","author":"Erspamer","year":"1952","journal-title":"Nature"},{"key":"B31","doi-asserted-by":"publisher","first-page":"5624","DOI":"10.3390\/ijms21165624","article-title":"Involvement of p38 MAPK in synaptic function and dysfunction","volume":"21","author":"Falcicchia","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1358","DOI":"10.1038\/mp.2015.168","article-title":"Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression","volume":"21","author":"Felger","year":"2016","journal-title":"Mol. Psychiatry"},{"key":"B33","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1007\/s00213-008-1268-7","article-title":"Neurochemical, behavioral and physiological effects of pharmacologically enhanced serotonin levels in serotonin transporter (SERT)-deficient mice","volume":"201","author":"Fox","year":"2008","journal-title":"Psychopharmacology"},{"key":"B34","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1097\/MED.0b013e32835bc703","article-title":"5-Hydroxytryptamine (serotonin) in the gastrointestinal tract","volume":"20","author":"Gershon","year":"2013","journal-title":"Curr Opin. Endocrinol. Diabetes Obes."},{"key":"B35","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1038\/86948","article-title":"Screening a large reference sample to identify very low frequency sequence variants: comparisons between two genes","volume":"27","author":"Glatt","year":"2001","journal-title":"Nat. Genet."},{"key":"B36","doi-asserted-by":"publisher","first-page":"712.e1","DOI":"10.1016\/j.jaac.2012.04.010","article-title":"Examining autism spectrum disorders by biomarkers: example from the oxytocin and serotonin systems","volume":"51","author":"Hammock","year":"2012","journal-title":"J. Am. Acad. Child Adolesc. Psychiatry"},{"key":"B37","doi-asserted-by":"publisher","first-page":"738","DOI":"10.1016\/0006-3223(91)90193-p","article-title":"Whole blood serotonin in juvenile obsessive-compulsive disorder","volume":"29","author":"Hanna","year":"1991","journal-title":"Biol. Psychiatry"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1016\/s0306-4522(97)00444-2","article-title":"Serotonin transporter messenger RNA in the developing rat brain: early expression in serotonergic neurons and transient expression in non-serotonergic neurons","volume":"83","author":"Hansson","year":"1998","journal-title":"Neuroscience"},{"key":"B39","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1126\/science.6093252","article-title":"Serotonin selectively inhibits growth cone motility and synaptogenesis of specific identified neurons","volume":"226","author":"Haydon","year":"1984","journal-title":"Science"},{"key":"B40","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1126\/science.1948036","article-title":"Cloning of a serotonin transporter affected by antidepressants","volume":"254","author":"Hoffman","year":"1991","journal-title":"Science"},{"key":"B41","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1002\/ajmg.b.30720","article-title":"Autism and serotonin transporter gene polymorphisms: A systematic review and meta-analysis","volume":"147","author":"Huang","year":"2008","journal-title":"Am. J. Med. Genet. B Neuropsychiatr. Genet."},{"key":"B42","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.phrs.2018.12.023","article-title":"Reprint of: serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders","volume":"140","author":"Israelyan","year":"2019","journal-title":"Pharmacol. Res."},{"key":"B43","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1016\/j.pnpbp.2014.09.004","article-title":"SLC6A4 markers modulate platelet 5-HT level and specific behaviors of autism: a study from an Indian population","volume":"56","author":"Jaiswal","year":"2015","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"B44","doi-asserted-by":"publisher","first-page":"2077","DOI":"10.1124\/mol.104.009555","article-title":"Evidence for biphasic effects of protein kinase C on serotonin transporter function, endocytosis and phosphorylation","volume":"67","author":"Jayanthi","year":"2005","journal-title":"Mol. Pharmacol."},{"key":"B45","first-page":"217","article-title":"Autistic disturbances of affective contact","volume":"2","author":"Kanner","year":"1943","journal-title":"Nerv. Child"},{"key":"B46","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1186\/2040-2392-4-35","article-title":"Genetic background modulates phenotypes of serotonin transporter Ala56 knock-in mice","volume":"4","author":"Kerr","year":"2013","journal-title":"Mol. Autism"},{"key":"B47","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1124\/mol.64.2.440","article-title":"A human serotonin transporter mutation causes constitutive activation of transport activity","volume":"64","author":"Kilic","year":"2003","journal-title":"Mol. Pharmacol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1001\/archgenpsychiatry.2009.30","article-title":"Lack of efficacy of citalopram in children with autism spectrum disorders and high levels of repetitive behavior: citalopram ineffective in children with autism","volume":"66","author":"King","year":"2009","journal-title":"Arch. Gen. Psychiatry"},{"key":"B49","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1093\/hmg\/ddm376","article-title":"Recurrent 16p11.2 microdeletions in autism","volume":"17","author":"Kumar","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"B50","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1159\/000112549","article-title":"Serotonin as a differentiation signal in early neurogenesis","volume":"1","author":"Lauder","year":"1978","journal-title":"Dev. Neurosci."},{"key":"B51","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1002\/(SICI)1096-9861(19981130)401:4<506::AID-CNE5>3.0.CO;2-#","article-title":"Transient developmental expression of monoamine transporters in the rodent forebrain","volume":"401","author":"Lebrand","year":"1998","journal-title":"J. Comp. Neurol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1002\/cne.21137","article-title":"Transitory uptake of serotonin in the developing sensory pathways of the common marmoset","volume":"499","author":"Lebrand","year":"2006","journal-title":"J. Comp. Neurol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1007\/BF01276434","article-title":"Organization of the human serotonin transporter gene","volume":"95","author":"Lesch","year":"1994","journal-title":"J. Neural Transm. Gen. Sect."},{"key":"B53","doi-asserted-by":"publisher","first-page":"1527","DOI":"10.1126\/science.274.5292.1527","article-title":"Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region","volume":"274","author":"Lesch","year":"1996","journal-title":"Science"},{"key":"B55","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/0006-3223(94)00147-U","article-title":"Primary structure of the serotonin transporter in unipolar depression and bipolar disorder","volume":"37","author":"Lesch","year":"1995","journal-title":"Biol. Psychiatry"},{"key":"B56","doi-asserted-by":"publisher","first-page":"2319","DOI":"10.1111\/j.1471-4159.1993.tb03522.x","article-title":"Primary structure of the human platelet serotonin uptake site: identity with the brain serotonin transporter","volume":"60","author":"Lesch","year":"1993","journal-title":"J. Neurochem."},{"key":"B57","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1007\/BF02216055","article-title":"Relationships of whole blood serotonin and plasma norepinephrine within families","volume":"20","author":"Leventhal","year":"1990","journal-title":"J. Autism Dev. Disord."},{"key":"B58","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.immuni.2018.12.012","article-title":"Cell-type-specific interleukin 1 receptor 1 signaling in the brain regulates distinct neuroimmune activities","volume":"50","author":"Liu","year":"2019","journal-title":"Immunity"},{"key":"B59","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1016\/j.bbi.2012.01.011","article-title":"Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism","volume":"26","author":"Malkova","year":"2012","journal-title":"Brain Behav. Immun."},{"key":"B60","doi-asserted-by":"publisher","first-page":"2221","DOI":"10.1172\/JCI84877","article-title":"Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function","volume":"126","author":"Margolis","year":"2016","journal-title":"J. Clin. Invest."},{"key":"B61","doi-asserted-by":"publisher","first-page":"1673","DOI":"10.1007\/s10803-017-3084-6","article-title":"Association of rigid-compulsive behavior with functional constipation in autism spectrum disorder","volume":"47","author":"Marler","year":"2017","journal-title":"J. Autism Dev. Disord."},{"key":"B62","doi-asserted-by":"publisher","first-page":"2015","DOI":"10.1038\/npp.2015.51","article-title":"Integrin \u03b23 haploinsufficiency modulates serotonin transport and antidepressant-sensitive behavior in mice","volume":"40","author":"Mazalouskas","year":"2015","journal-title":"Neuropsychopharmacology"},{"key":"B63","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1002\/ajmg.b.20151","article-title":"Linkage and association analysis at the serotonin transporter (SLC6A4) locus in a rigid-compulsive subset of autism","volume":"127","author":"McCauley","year":"2004","journal-title":"Am. J. Med. Genet. B Neuropsychiatr. Genet."},{"key":"B2010","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1016\/0006-3223(93)90011-2","article-title":"Acute tryptophan depletion in autistic disorder: a controlled case study","volume":"33","author":"McDougle","year":"1993","journal-title":"Biol. Psychiatry"},{"key":"B102","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1001\/archpsyc.1996.01830110029004","article-title":"Effects of tryptophan depletion in drug-free adults with autistic disorder","volume":"53","author":"McDougle","year":"1996","journal-title":"Arch. Gen. Psychiatry"},{"key":"B64","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1542\/peds.2013-3995","article-title":"Gastrointestinal symptoms in autism spectrum disorder: a meta-analysis","volume":"133","author":"McElhanon","year":"2014","journal-title":"Pediatrics"},{"key":"B65","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1097\/00004583-199011000-00032","article-title":"Fluoxetine and autism","volume":"29","author":"Mehlinger","year":"1990","journal-title":"J. Am. Acad. Child Adolesc. Psychiatry"},{"key":"B204","doi-asserted-by":"publisher","first-page":"e12660","DOI":"10.1111\/gbb.12660","article-title":"Using the tools of genetic epidemiology to understand sex differences in neuropsychiatric disorders","volume":"19","author":"Merikangas","year":"2020","journal-title":"Genes, Brain and Behav."},{"key":"B66","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1177\/0269881198012003041","article-title":"Selective serotonin reuptake inhibitors in the acute treatment of depression","volume":"12","author":"Montgomery","year":"1995","journal-title":"J. Psychopharmacol."},{"key":"B67","doi-asserted-by":"publisher","first-page":"1263","DOI":"10.1002\/mds.25460","article-title":"Common and rare alleles of the serotonin transporter gene, SLC6A4, associated with Tourette\u2019s disorder","volume":"28","author":"Moya","year":"2013","journal-title":"Mov. Disord."},{"key":"B68","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1038\/npp.2016.166","article-title":"Impact of maternal serotonin transporter genotype on placental serotonin, fetal forebrain serotonin and neurodevelopment","volume":"42","author":"Muller","year":"2017","journal-title":"Neuropsychopharmacology"},{"key":"B69","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.neuroscience.2015.11.010","article-title":"The serotonin system in autism spectrum disorder: from biomarker to animal models","volume":"321","author":"Muller","year":"2016","journal-title":"Neuroscience"},{"key":"B70","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.coph.2011.02.008","article-title":"Human serotonin transporter gene (SLC6A4) variants: their contributions to understanding pharmacogenomic and other functional G\u00d7G and G\u00d7E differences in health and disease","volume":"11","author":"Murphy","year":"2011","journal-title":"Curr. Opin. Pharmacol."},{"key":"B72","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1515\/jbcpp-2020-0338","article-title":"Serotonin, tryptophan metabolism and the brain-gut-microbiome axis","volume":"277","author":"O\u2019Mahony","year":"2015","journal-title":"Behav. Brain Res."},{"key":"B71","doi-asserted-by":"publisher","first-page":"1111","DOI":"10.1007\/s00213-020-05758-8","article-title":"Serotonin 5-HT(1B) receptor-mediated behavior and binding in mice with the overactive and dysregulated serotonin transporter Ala56 variant","volume":"238","author":"O\u2019Reilly","year":"2021","journal-title":"Psychopharmacology (Berl)"},{"key":"B73","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1002\/(SICI)1520-6394(1998)8:1+<5::AID-DA2>3.0.CO;2-I","article-title":"The serotonin transporter and depression","volume":"8","author":"Owens","year":"1998","journal-title":"Depress. Anxiety"},{"key":"B74","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1038\/sj.mp.4001365","article-title":"Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype","volume":"8","author":"Ozaki","year":"2003","journal-title":"Mol. Psychiatry"},{"key":"B75","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41398-020-01125-5","article-title":"Decreased phenol sulfotransferase activities associated with hyperserotonemia in autism spectrum disorders","volume":"11","author":"Pagan","year":"2021","journal-title":"Transl. Psychiatry"},{"key":"B77","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1007\/BF02206997","article-title":"Platelet serotonin, a possible marker for familial autism","volume":"21","author":"Piven","year":"1991","journal-title":"J. Autism Dev. Disord."},{"key":"B78","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1098\/rstb.2008.0143","article-title":"Enhanced activity of human serotonin transporter variants associated with autism","volume":"364","author":"Prasad","year":"2009","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"B79","doi-asserted-by":"publisher","first-page":"11545","DOI":"10.1073\/pnas.0501432102","article-title":"Human serotonin transporter variants display altered sensitivity to protein kinase G and p38 mitogen-activated protein kinase","volume":"102","author":"Prasad","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"B80","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1523\/JNEUROSCI.17-01-00045.1997","article-title":"Protein kinase C activation regulates human serotonin transporters in HEK-293 cells via altered cell surface expression","volume":"17","author":"Qian","year":"1997","journal-title":"J. Neurosci."},{"key":"B81","doi-asserted-by":"publisher","first-page":"3249","DOI":"10.1021\/acschemneuro.8b00689","article-title":"Human serotonin transporter coding variation establishes conformational bias with functional consequences","volume":"10","author":"Quinlan","year":"2019","journal-title":"ACS Chem. Neurosci."},{"key":"B82","doi-asserted-by":"publisher","first-page":"89","DOI":"10.3389\/fnmol.2020.00089","article-title":"Ex vivo quantitative proteomic analysis of serotonin transporter interactome: network impact of the SERT Ala56 coding variant","volume":"13","author":"Quinlan","year":"2020","journal-title":"Front. Mol. Neurosci."},{"key":"B83","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1007\/s11920-011-0232-0","article-title":"Is depression an inflammatory disorder?","volume":"13","author":"Raison","year":"2011","journal-title":"Curr. Psychiatry Rep."},{"key":"B84","doi-asserted-by":"publisher","first-page":"2542","DOI":"10.1073\/pnas.90.6.2542","article-title":"Antidepressant-and cocaine-sensitive human serotonin transporter: molecular cloning, expression and chromosomal localization","volume":"90","author":"Ramamoorthy","year":"1993","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"B85","doi-asserted-by":"publisher","first-page":"2458","DOI":"10.1074\/jbc.273.4.2458","article-title":"Phosphorylation and regulation of antidepressant-sensitive serotonin transporters","volume":"273","author":"Ramamoorthy","year":"1998","journal-title":"J. Biol. Chem."},{"key":"B86","doi-asserted-by":"publisher","first-page":"11639","DOI":"10.1074\/jbc.M611353200","article-title":"Phosphorylation of threonine residue 276 is required for acute regulation of serotonin transporter by cyclic GMP","volume":"282","author":"Ramamoorthy","year":"2007","journal-title":"J. Biol. Chem."},{"key":"B87","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1016\/j.pharmthera.2010.09.009","article-title":"Regulation of monoamine transporters: role of transporter phosphorylation","volume":"129","author":"Ramamoorthy","year":"2011","journal-title":"Pharmacol. Ther."},{"key":"B88","doi-asserted-by":"publisher","first-page":"E10245","DOI":"10.1073\/pnas.1809137115","article-title":"p38\u03b1 MAPK signaling drives pharmacologically reversible brain and gastrointestinal phenotypes in the SERT Ala56 mouse","volume":"115","author":"Robson","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"B89","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1007\/BF00431264","article-title":"Platelet uptake of serotonin in psychotic children","volume":"67","author":"Rotman","year":"1980","journal-title":"Psychopharmacology"},{"key":"B90","doi-asserted-by":"publisher","first-page":"5298","DOI":"10.1021\/acs.jmedchem.9b00058","article-title":"A selective and brain penetrant p38\u03b1MAPK inhibitor candidate for neurologic and neuropsychiatric disorders that attenuates neuroinflammation and cognitive dysfunction","volume":"62","author":"Roy","year":"2019","journal-title":"J. Med. Chem."},{"key":"B91","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1002\/aur.30","article-title":"A large-scale screen for coding variants in SERT\/SLC6A4 in autism spectrum disorders","volume":"1","author":"Sakurai","year":"2008","journal-title":"Autism Res."},{"key":"B92","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1016\/s0022-3476(61)80261-8","article-title":"Studies on 5-hydroxyindole metabolism in autistic and other mentally retarded children","volume":"58","author":"Schain","year":"1961","journal-title":"J. Pediatr."},{"key":"B93","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1111\/j.1749-6632.1996.tb17446.x","article-title":"Drug targets in the embryo: studies on the cocaine-and antidepressant-sensitive serotonin transporter","volume":"801","author":"Schroeter","year":"1996","journal-title":"Ann. N Y Acad. Sci."},{"key":"B94","doi-asserted-by":"publisher","first-page":"1417","DOI":"10.1002\/aur.1791","article-title":"Is there sexual dimorphism of hyperserotonemia in autism spectrum disorder?","volume":"10","author":"Shuffrey","year":"2017","journal-title":"Autism Res."},{"key":"B95","doi-asserted-by":"publisher","first-page":"e1067","DOI":"10.1038\/tp.2017.17","article-title":"An autism-associated serotonin transporter variant disrupts multisensory processing","volume":"7","author":"Siemann","year":"2017","journal-title":"Transl. Psychiatry"},{"key":"B96","doi-asserted-by":"publisher","first-page":"1430","DOI":"10.1002\/aur.2375","article-title":"Approaches to understanding multisensory dysfunction in autism spectrum disorder","volume":"13","author":"Siemann","year":"2020","journal-title":"Autism Res."},{"key":"B97","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1038\/s41380-018-0260-9","article-title":"SSRIs target prefrontal to raphe circuits during development modulating synaptic connectivity and emotional behavior","volume":"24","author":"Soiza-Reilly","year":"2019","journal-title":"Mol. Psychiatry"},{"key":"B98","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1086\/432648","article-title":"Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors","volume":"77","author":"Sutcliffe","year":"2005","journal-title":"Am J. Hum. Genet."},{"key":"B99","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1007\/BF01537909","article-title":"Reassessment of elevated serotonin levels in blood platelets in early infantile autism","volume":"6","author":"Takahashi","year":"","journal-title":"J. Autism Child. Schizophr."},{"key":"B100","doi-asserted-by":"publisher","first-page":"1645","DOI":"10.1016\/0024-3205(76)90069-2","article-title":"Acute phase proteins and pesticide exposure","volume":"19","author":"Takahashi","year":"","journal-title":"Life Sci."},{"key":"B101","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.1176\/ajp.148.8.1089b","article-title":"Fluoxetine in autism","volume":"148","author":"Todd","year":"1991","journal-title":"Am. J. Psychiatry"},{"key":"B1020","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1007\/s11689-009-9020-0","article-title":"Modeling rare gene variation to gain insight into the oldest biomarker in autism: construction of the serotonin transporter Gly56Ala knock-in mouse","volume":"1","author":"Veenstra-VanderWeele","year":"2009","journal-title":"J. Neurodev. Disord."},{"key":"B103","doi-asserted-by":"publisher","first-page":"5469","DOI":"10.1073\/pnas.1112345109","article-title":"Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior","volume":"109","author":"Veenstra-VanderWeele","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"B104","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1038\/mp.2009.100","article-title":"Association of SLC6A4 variants with obsessive-compulsive disorder in a large multicenter US family study","volume":"16","author":"Voyiaziakis","year":"2011","journal-title":"Mol. Psychiatry"},{"key":"B105","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1016\/0361-9230(83)90144-2","article-title":"Development of the serotonergic system in the rat embryo: an immunocytochemical study","volume":"10","author":"Wallace","year":"1983","journal-title":"Brain Res. Bull."},{"key":"B106","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1038\/s41586-018-0416-4","article-title":"5-HT release in nucleus accumbens rescues social deficits in mouse autism model","volume":"560","author":"Walsh","year":"2018","journal-title":"Nature"},{"key":"B107","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1086\/426697","article-title":"Sex-specific genetic architecture of whole blood serotonin levels","volume":"76","author":"Weiss","year":"2005","journal-title":"Am J. Hum. Genet."},{"key":"B108","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1097\/YPG.0b013e3282f08a06","article-title":"SERT Ileu425Val in autism, asperger syndrome and obsessive\u2013compulsive disorder","volume":"18","author":"Wendland","year":"2008","journal-title":"Psychiatr. Genet."},{"key":"B109","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.neuroscience.2011.08.056","article-title":"Natural and engineered coding variation in antidepressant-sensitive serotonin transporters","volume":"197","author":"Ye","year":"2011","journal-title":"Neuroscience"},{"key":"B110","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1111\/gbb.12092","article-title":"Evaluation of heritable determinants of blood and brain serotonin homeostasis using recombinant inbred mice","volume":"13","author":"Ye","year":"2014","journal-title":"Genes Brain Behav."},{"key":"B113","doi-asserted-by":"publisher","first-page":"2121","DOI":"10.1038\/sj.npp.1301029","article-title":"The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters","volume":"31","author":"Zhu","year":"2006","journal-title":"Neuropsychopharmacology"},{"key":"B111","doi-asserted-by":"publisher","first-page":"1462","DOI":"10.1124\/mol.65.6.1462","article-title":"Adenosine receptor, protein kinase G and p38 mitogen-activated protein kinase-dependent up-regulation of serotonin transporters involves both transporter trafficking and activation","volume":"65","author":"Zhu","year":"2004","journal-title":"Mol. Pharmacol."},{"key":"B112","doi-asserted-by":"publisher","first-page":"2510","DOI":"10.1038\/npp.2010.116","article-title":"Interleukin-1 receptor activation by systemic lipopolysaccharide induces behavioral despair linked to MAPK regulation of CNS serotonin transporters","volume":"35","author":"Zhu","year":"2010","journal-title":"Neuropsychopharmacology"},{"key":"B115","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1124\/jpet.107.121665","article-title":"Rapid stimulation of presynaptic serotonin transport by a3 adenosine receptors","volume":"322","author":"Zhu","year":"2007","journal-title":"J. Pharmacol. Exp. Ther."}],"container-title":["Frontiers in Cellular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2021.677563\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,3]],"date-time":"2021-06-03T23:30:15Z","timestamp":1622763015000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2021.677563\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,3]]},"references-count":116,"alternative-id":["10.3389\/fncel.2021.677563"],"URL":"https:\/\/doi.org\/10.3389\/fncel.2021.677563","relation":{},"ISSN":["1662-5102"],"issn-type":[{"value":"1662-5102","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,3]]},"article-number":"677563"}}