Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function

Journal of Clinical Investigation

Volumn 126, Issue 6, 2016, Pages 2221-2235

  Margolis, Kara Gross ^a   Li, Zhishan ^a   Stevanovic, Korey ^a   Saurman, Virginia ^a   Israelyan, Narek ^a   Anderson, George M ^b   Snyder, Isaac ^a   Veenstra VanderWeele, Jeremy ^a   Blakely, Randy D ^c   Gershon, Michael D ^a  

^a Division of Pediatric Gastroenterology ^*  (United States)

^b YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c VANDERBILT UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 AMINOBUTYRIC ACID; CALCITONIN GENE RELATED PEPTIDE; FLUOXETINE; PRUCALOPRIDE; SEROTONIN TRANSPORTER; SEROTONIN TRANSPORTER ALA56; TYROSINE 3 MONOOXYGENASE; UNCLASSIFIED DRUG; SEROTONIN; SLC6A4 PROTEIN, HUMAN; SLC6A4 PROTEIN, MOUSE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; AUTISM; CELL DENSITY; CELL PROLIFERATION; CONTROLLED STUDY; CRYPT CELL; DEVELOPMENTAL DISORDER; FEMALE; GASTROINTESTINAL MALFORMATION; GASTROINTESTINAL MOTILITY; GASTROINTESTINAL TRACT FUNCTION; GENE MUTATION; HYPOPLASIA; INTESTINE EPITHELIUM CELL; INTESTINE INNERVATION; INTESTINE MUCOSA PERMEABILITY; INTESTINE PRESSURE; INTESTINE TRANSIT TIME; MOUSE; MYENTERIC PLEXUS; NERVOUS SYSTEM DEVELOPMENT; NONHUMAN; PERISTALSIS; PHENOTYPE; PRIORITY JOURNAL; PROTEIN EXPRESSION; RECEPTOR DOWN REGULATION; SEROTONINERGIC NERVE CELL; SIGNAL TRANSDUCTION; STOMACH EMPTYING; 129 MOUSE; ABNORMALITIES; ANIMAL; AUTISM SPECTRUM DISORDER; C57BL MOUSE; DEFICIENCY; GASTROINTESTINAL TRACT; GENETIC VARIATION; GENETICS; GROWTH, DEVELOPMENT AND AGING; HUMAN; KNOCKOUT MOUSE; MALE; METABOLISM; MUTANT MOUSE STRAIN; PATHOPHYSIOLOGY; PHYSIOLOGY; PREGNANCY;

ANIMALS; AUTISM SPECTRUM DISORDER; ENTERIC NERVOUS SYSTEM; FEMALE; GASTROINTESTINAL MOTILITY; GASTROINTESTINAL TRACT; GENETIC VARIATION; HUMANS; MALE; MICE; MICE, 129 STRAIN; MICE, INBRED C57BL; MICE, KNOCKOUT; MICE, MUTANT STRAINS; MODELS, ANIMAL; NEUROGENESIS; PREGNANCY; SEROTONIN; SEROTONIN PLASMA MEMBRANE TRANSPORT PROTEINS;

EID: 84974653357     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI84877     Document Type: Article

References (76)

1. Posar A, Resca F, Visconti P. Autism according to diagnostic and statistical manual of mental disorders 5(th) edition: the need for further improvements. J Pediatr Neurosci. 2015;10(2):146-148.
2. McElhanon BO, McCracken C, Karpen S, Sharp WG. Gastrointestinal symptoms in autism spectrum disorder: a meta-analysis. Pediatrics. 2014;133(5):872-883.
3. Matondo RB, et al. Deletion of the serotonin transporter in rats disturbs serotonin homeostasis without impairing liver regeneration. Am J Physiol Gastrointest Liver Physiol. 2009;296(4):G963-G968.
4. Mulder EJ, et al. Platelet serotonin levels in pervasive developmental disorders and mental retardation: diagnostic group differences, within-group distribution, and behavioral correlates. J Am Acad Child Adolesc Psychiatry. 2004;43(4):491-499.
5. Ritvo ER, Yuwiler A, Geller E, Ornitz EM, Saeger K, Plotkin S. Increased blood serotonin and platelets in early infantile autism. Arch Gen Psychiatry. 1970;23(6):566-572.
6. Morrissey JJ, Walker MN, Lovenberg W. The absence of tryptophan hydroxylase activity in blood platelets. Proc Soc Exp Biol Med. 1977;154(4):496-499.
7. Lesch KP, Wolozin BL, Murphy DL, Riederer P. Primary structure of the human platelet serotonin (5-HT) uptake site: Identity with the brain 5-HT transporter. J Neurochem. 1993;60(6):2319-2322.
8. Hughes FB, Brodie BB. The mechanism of serotonin and catecholamine uptake by platelets. J Pharmacol Exp Ther. 1959;127:96-102.
9. Prasad HC, et al. Human serotonin transporter variants display altered sensitivity to protein kinase G and p38 mitogen-activated protein kinase. Proc Natl Acad Sci U S A. 2005;102(32):11545-11550.
10. Sutcliffe JS, et al. Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors. Am J Hum Genet. 2005;77(2):265-279.
11. Prasad HC, Steiner JA, Sutcliffe JS, Blakely RD. Enhanced activity of human serotonin transporter variants associated with autism. Philos Trans R Soc Lond B Biol Sci. 2009;364(1514):163-173.
12. Veenstra-Vanderweele J, et al. 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. 2009;1(2):158-171.
13. Veenstra-VanderWeele J, et al. Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior. Proc Natl Acad Sci U S A. 2012;109(14):5469-5474.
14. Gaspar P, Cases O, Maroteaux L. The developmental role of serotonin: news from mouse molecular genetics. Nat Rev Neurosci. 2003;4(12):1002-1012.
15. Kepser LJ, Homberg JR. The neurodevelopmental effects of serotonin: a behavioural perspective. Behav Brain Res. 2015;277:3-13.
16. Liu C, Maejima T, Wyler SC, Casadesus G, Herlitze S, Deneris ES. Pet-1 is required across different stages of life to regulate serotonergic function. Nat Neurosci. 2010;13(10):1190-1198.
17. Gershon MD. 5-Hydroxytryptamine (serotonin) in the gastrointestinal tract. Curr Opin Endocrinol Diabetes Obes. 2013;20(1):14-21.
18. Chen JJ, et al. Maintenance of serotonin in the intestinal mucosa and ganglia of mice that lack the high affinity serotonin transporter (SERT): abnormal intestinal motility and the expression of cation transporters. J Neurosci. 2001;21(16):6348-6361.
19. Wade PR, Chen J, Jaffe B, Kassem IS, Blakely RD, Gershon MD. Localization and function of a 5-HT transporter in crypt epithelia of the gastrointestinal tract. J Neurosci. 1996;16(7):2352-2364.
20. Blakely RD, et al. Cloning and expression of a functional serotonin transporter from rat brain. Nature. 1991;354(6348):66-70.
21. Chen JX, Pan H, Rothman TP, Wade PR, Gershon MD. Guinea pig 5-HT transporter: cloning, expression, distribution and function in intestinal sensory reception. Am J Physiol. 1998;275(3 pt 1):G433-G448.
22. Li Z, et al. Essential roles of enteric neuronal serotonin in gastrointestinal motility and the development/survival of enteric dopaminergic neurons. J Neurosci. 2011;31(24):8998-9009.
23. Margolis KG, et al. Pharmacological reduction of mucosal but not neuronal serotonin opposes inflammation in mouse intestine. Gut. 2014;63(6):928-937.
24. Heredia DJ, Gershon MD, Koh SD, Corrigan RD, Okamoto T, Smith TK. Important role of mucosal serotonin in colonic propulsion and peristaltic reflexes: in vitro analyses in mice lacking tryptophan hydroxylase 1. J Physiol. 2013;591(23):5939-5957.
25. Hillsley K, Grundy D. Sensitivity to 5-hydroxytryptamine in different afferent subpopulations within mesenteric nerves supplying the rat jejunum. J Physiol. 1998;509(pt 3):717-727.
26. Blackshaw LA, Grundy D. Effects of 5-hydroxytryptamine on discharge of vagal mucosal afferent fibres from the upper gastrointestinal tract of the ferret. J Auton Nerv Syst. 1993;45(1):41-50.
27. Lang IM. Noxious stimulation of emesis. Dig Dis Sci. 1999;44(8 suppl):58S-63S.
28. Pan H, Gershon MD. Activation of intrinsic afferent pathways in submucosal ganglia of the guinea pig small intestine. J Neurosci. 2000;20(9):3295-3309.
29. Bertrand PP, Kunze WAA, Furness JB, Bornstein JC. The terminals of myenteric intrinsic primary afferent neurons of the guinea pig ileum are excited by 5-HT acting at 5-HT3 receptors. Neuroscience. 2000;101(2):459-469.
30. Bülbring E, Crema A. The release of 5-hydroxytryptamine in relation to pressure exerted on the intestinal mucosa. J Physiol. 1959;146(1):18-28.
31. Cooke HJ, Christofi FL. Enteric regulation of mucosal secretion. In: Johnson LR, ed. Physiology of the Gastrointestinal Tract. 4th ed. New York, New York, USA: Academic Press; 2006:737-762.
32. Liu MT, Kuan YH, Wang J, Hen R, Gershon MD. 5-HT4 receptor-mediated neuroprotection and neurogenesis in the enteric nervous system of adult mice. J Neurosci. 2009;29(31):9683-9699.
33. Gross ER, Gershon MD, Margolis KG, Gertsberg ZV, Cowles RA. Neuronal serotonin regulates growth of the intestinal mucosa in mice. Gastroenterology. 2012;143(2):408-417.
34. Briejer MR, et al. The in vitro pharmacological profile of prucalopride, a novel enterokinetic compound. Eur J Pharmacol. 2001;423(1):71-83.
35. Karaosmanoglu T, Aygun B, Wade PR, Gershon MD. Regional differences in the number of neurons in the myenteric plexus of the guinea pig small intestine and colon: an evaluation of markers used to count neurons. Anat Rec. 1996;244(4):470-480.
36. Chalazonitis A, et al. Bone morphogenetic protein regulation of enteric neuronal phenotypic diversity: relationship to timing of cell cycle exit. J Comp Neurol. 2008;509(5):474-492.
37. Pham TD, Gershon MD, Rothman TP. Time of origin of neurons in the murine enteric nervous system. J Comp Neurol. 1991;314(4):789-798.
38. Bonnin A, et al. A transient placental source of serotonin for the fetal forebrain. Nature. 2011;472(7343):347-350.
39. Yamataka A, et al. Intestinal neuronal dysplasia-like pathology in Ncx/Hox11L. J Pediatr Surg. 2001;36(8):1293-1296.
40. Spencer NJ, Bywater RA, Taylor GS. Evidence that myoelectric complexes in the isolated mouse colon may not be of myogenic origin. Neurosci Lett. 1998;250(3):153-156.
41. Misiewicz JJ, Waller SL, Eisner M. Motor responses of human gastrointestinal tract to 5-hydroxytryptamine in vivo and in vitro. Gut. 1966;7(3):208-216.
42. Oosterbosch L, von der Ohe M, Valdovinos MA, Kost LJ, Phillips SF, Camilleri M. Effects of serotonin on rat ileocolonic transit and fluid transfer in vivo: possible mechanisms of action. Gut. 1993;34(6):794-798.
43. Adamec R, Burton P, Blundell J, Murphy DL, Holmes A. Vulnerability to mild predator stress in serotonin transporter knockout mice. Behav Brain Res. 2006;170(1):126-140.
44. Smith TK, Gershon MD. CrossTalk proposal: 5-HT is necessary for peristalsis. J Physiol. 2015;593(15):3225-3227.
45. Kerr TM, et al. Genetic background modulates phenotypes of serotonin transporter Ala56 knock-in mice. Mol Autism. 2013;4(1):35.
46. Kawasaki H. Spatio-temporal regulation of the formation of the somatosensory system. Dev Growth Differ. 2015;57(3):193-199.
47. Chen X, Ye R, Gargus JJ, Blakely RD, Dobrenis K, Sze JY. Disruption of transient serotonin accumulation by non-serotonin-producing neurons impairs cortical map development [published online ahead of print January 14, 2015]. Cell Rep. doi:10.1016/j.celrep.2014.12.033.
48. Deneris ES. Molecular genetics of mouse serotonin neurons across the lifespan. Neuroscience. 2011;197:17-27.
49. Fiorica-Howells E, Maroteaux L, Gershon MD. Serotonin and the 5-HT(2B) receptor in the development of enteric neurons. J Neurosci. 2000;20(1):294-305.
50. Furness JB, Costa M. Neurons with 5-hydroxytryptamine-like immunoreactivity in the enteric nervous system: Their projections in the guinea pig small intestine. Neuroscience. 1982;7(2):341-350.
51. Qu ZD, Thacker M, Castelucci P, Bagyanszki M, Epstein ML, Furness JB. Immunohistochemical analysis of neuron types in the mouse small intestine. Cell Tissue Res. 2008;334(2):147-161.
52. Clevers H. The intestinal crypt, a prototype stem cell compartment. Cell. 2013;154(2):274-284.
53. Wogelius P, et al. Maternal use of selective serotonin reuptake inhibitors and risk of congenital malformations. Epidemiology. 2006;17(6):701-704.
54. Nijenhuis CM, ter Horst PG, van Rein N, Wilffert B, de Jong-van den Berg LT. Disturbed development of the enteric nervous system after in utero exposure of selective serotonin re-uptake inhibitors and tricyclic antidepressants. Br J Clin Pharmacol. 2012;73(1):126-134.
55. Gershon MD. Nerves, reflexes, and the enteric nervous system: pathogenesis of the irritable bowel syndrome. J Clin Gastroenterol. 2005;39(5 suppl 3):S184-S193.
56. Margolis KG, et al. Enteric neuronal density contributes to the severity of intestinal inflammation. Gastroenterology. 2011;141(2):588-598.
57. Persico AM, Napolioni V. Autism genetics. Behav Brain Res. 2013;251:95-112.
58. Devlin B, et al. Autism and the serotonin transporter: the long and short of it. Mol Psychiatry. 2005;10(12):1110-1116.
59. Huang CH, Santangelo SL. Autism and serotonin transporter gene polymorphisms: a systematic review and meta-analysis. Am J Med Genet B Neuropsychiatr Genet. 2008;147B(6):903-913.
60. Kistner-Griffin E, Brune CW, Davis LK, Sutcliffe JS, Cox NJ, Cook EH Jr. Parent-of-origin effects of the serotonin transporter gene associated with autism. Am J Med Genet B Neuropsychiatr Genet. 2011;156(2):139-144.
61. Veenstra-VanderWeele J, et al. Transmission disequilibrium studies of the serotonin 5-HT2A receptor gene (HTR2A) in autism. Am J Med Genet. 2002;114(3):277-283.
62. Hsiao EY. Gastrointestinal issues in autism spectrum disorder. Harv Rev Psychiatry. 2014;22(2):104-111.
63. Schulze TG, McMahon FJ. Defining the phenotype in human genetic studies: forward genetics and reverse phenotyping. Hum Hered. 2004;58(3-4):131-138.
64. Imoto Y, et al. Role of the 5-HT4 receptor in chronic fluoxetine treatment-induced neurogenic activity and granule cell dematuration in the dentate gyrus. Mol Brain. 2015;8:29.
65. King PH, Redden D, Palmgren JS, Nabors LB, Lennon VA. Hu antigen specificities of ANNA-I autoantibodies in paraneoplastic neurological disease. J Autoimmun. 1999;13(4):435-443.
66. Lennon VA. The case for a descriptive generic nomenclature: clarification of immunostaining criteria for PCA-1, ANNA-1, and ANNA-2 autoantibodies. Neurology. 1994;44(12):2412-2415.
67. Chu G, Wilson PC, Carter CD, Lennon VA, Roberts-Thomson IC. Intestinal pseudo-obstruction, type 1 anti-neuronal nuclear antibodies and small-cell carcinoma of the lung. J Gastroenterol Hepatol. 1993;8(6):604-606.
68. Chalk CH, Lennon VA, Stevens JC, Windebank AJ. Seronegativity for type 1 antineuronal nuclear antibodies ('anti-Hu') in subacute sensory neuronopathy patients without cancer. Neurology. 1993;43(11):2209-2211.
69. Li ZS, Schmauss C, Cuenca A, Ratcliffe E, Gershon MD. Physiological modulation of intestinal motility by enteric dopaminergic neurons and the D2 receptor: analysis of dopamine receptor expression, location, development, and function in wild-type and knock-out mice. J Neurosci. 2006;26(10):2798-2807.
70. Kimball ES, Palmer JM, D'Andrea MR, Hornby PJ, Wade PR. Acute colitis induction by oil of mustard results in later development of an IBS-like accelerated upper GI transit in mice. Am J Physiol Gastrointest Liver Physiol. 2005;288(6):G1266-G1273.
71. Miller MS, Galligan JJ, Burks TF. Accurate measurement of intestinal transit in the rat. J Pharmacol Methods. 1981;6(3):211-217.
72. Roberts RR, Bornstein JC, Bergner AJ, Young HM. Disturbances of colonic motility in mouse models of Hirschsprung's disease. Am J Physiol Gastrointest Liver Physiol. 2008;294(4):G996-G1008.
73. Roberts RR, Murphy JF, Young HM, Bornstein JC. Development of colonic motility in the neonatal mouse-studies using spatiotemporal maps. Am J Physiol Gastrointest Liver Physiol. 2007;292(3):G930-G938.
74. Gwynne RM, Thomas EA, Goh SM, Sjovall H, Bornstein JC. Segmentation induced by intraluminal fatty acid in isolated guinea-pig duodenum and jejunum. J Physiol. 2004;556(pt 2):557-569.
75. Welch MG, Margolis KG, Li Z, Gershon MD. Oxytocin regulates gastrointestinal motility, inflammation, macromolecular permeability, and mucosal maintenance in mice. Am J Physiol Gastrointest Liver Physiol. 2014;307(8):G848-G862.
76. Chaniotou Z, et al. Corticotropin-releasing factor regulates TLR4 expression in the colon and protects mice from colitis. Gastroenterology. 2010;139(6):2083-2092.