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Lack of brain serotonin affects postnatal development and serotonergic neuronal circuitry formation.

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Migliarini, S. Pacini, G. Pelosi, Barbara [UCL] Lunardi, G. Pasqualetti, M.

Despite increasing evidence suggests that serotonin (5-HT) can influence neurogenesis, neuronal migration and circuitry formation, the precise role of 5-HT on central nervous system (CNS) development is only beginning to be elucidated. Moreover, how changes in serotonin homeostasis during critical developmental periods may have etiological relevance to human mental disorders, remains an unsolved question. In this study we address the consequences of 5-HT synthesis abrogation on CNS development using a knock-in mouse line in which the tryptophan hydroxylase 2 (Tph2) gene is replaced by the eGFP reporter. We report that lack of brain 5-HT results in a dramatic reduction of body growth rate and in 60% lethality within the first 3 weeks after birth, with no gross anatomical changes in the brain. Thanks to the specific expression of the eGFP, we could highlight the serotonergic system independently of 5-HT immunoreactivity. We found that lack of central serotonin produces severe abnormalities in the serotonergic circuitry formation with a brain region- and time- specific effect. Indeed, we observed a striking reduction of serotonergic innervation to the suprachiasmatic and thalamic paraventricular nuclei, while a marked serotonergic hyperinnervation was found in the nucleus accumbens and hippocampus of Tph2∷eGFP mutants. Finally, we demonstrated that BDNF expression is significantly up-regulated in the hippocampus of mice lacking brain 5-HT, mirroring the timing of the appearance of hyperinnervation and thus unmasking a possible regulatory feedback mechanism tuning the serotonergic neuronal circuitry formation. On the whole, these findings reveal that alterations of serotonin levels during CNS development affect the proper wiring of the brain that may produce long-lasting changes leading to neurodevelopmental disorders.

Document type Article de périodique (Journal article)
Publication date 2013
Language Anglais
Journal information "Molecular Psychiatry" - Vol. 18, no.10, p. 1106-1118 (2012)
Peer reviewed yes
Publisher Nature Publishing Group (London)
issn 1359-4184
e-issn 1476-5578
Publication status Publié
Affiliation University of Pisa - Department of Biology
MESH Subject Animals ; Longevity ; Mice ; Mice, Inbred C57BL ; Neural Pathways ; Neurites ; Neurogenesis ; Phenotype ; Serotonergic Neurons ; Serotonin ; Transgenes ; Body Size ; Tryptophan Hydroxylase ; Brain ; Brain Chemistry ; Brain-Derived Neurotrophic Factor ; Gene Knock-In Techniques ; Genes, Reporter ; Green Fluorescent Proteins ; Growth Disorders
Links
  1. Gross Cornelius, Hen Rene, The developmental origins of anxiety, 10.1038/nrn1429
  2. Lucki Irwin, The spectrum of behaviors influenced by serotonin, 10.1016/s0006-3223(98)00139-5
  3. Miczek K. A., de Almeida R. M. M., Kravitz E. A., Rissman E. F., de Boer S. F., Raine A., Neurobiology of Escalated Aggression and Violence, 10.1523/jneurosci.3500-07.2007
  4. Veenstra-VanderWeele Jeremy, Anderson George M, Cook Edwin H, Pharmacogenetics and the serotonin system: initial studies and future directions, 10.1016/s0014-2999(00)00814-1
  5. Lidov Hart G.W., Molliver Mark E., Immunohistochemical study of the development of serotonergic neurons in the rat CNS, 10.1016/0361-9230(82)90164-2
  6. Wallace James A., Lauder Jean M., Development of the serotonergic system in the rat embryo: An immunocytochemical study, 10.1016/0361-9230(83)90144-2
  7. Bonnin Alexandre, Goeden Nick, Chen Kevin, Wilson Melissa L., King Jennifer, Shih Jean C., Blakely Randy D., Deneris Evan S., Levitt Pat, A transient placental source of serotonin for the fetal forebrain, 10.1038/nature09972
  8. Cote F., Fligny C., Bayard E., Launay J.-M., Gershon M. D., Mallet J., Vodjdani G., Maternal serotonin is crucial for murine embryonic development, 10.1073/pnas.0606722104
  9. Gaspar Patricia, Cases Olivier, Maroteaux Luc, The developmental role of serotonin: news from mouse molecular genetics, 10.1038/nrn1256
  10. Lauder Jean M., Neurotransmitters as growth regulatory signals: role of receptors and second messengers, 10.1016/0166-2236(93)90162-f
  11. Chugani Diane C., Muzik Otto, Behen Michael, Rothermel Robert, Janisse James J., Lee Jennifer, Chugani Harry T., Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children, 10.1002/1531-8249(199903)45:3<287::aid-ana3>3.0.co;2-9
  12. Sodhi Monsheel S.K, Sanders-Bush Elaine, Serotonin and brain development, International Review of Neurobiology (2004) ISBN:9780123668608 p.111-174, 10.1016/s0074-7742(04)59006-2
  13. Whitaker-Azmitia Patricia M., Serotonin and brain development: role in human developmental diseases, 10.1016/s0361-9230(01)00615-3
  14. Cases Olivier, Vitalis Tania, Seif Isabelle, De Maeyer Edward, Sotelo Constantino, Gaspar Patricia, Lack of Barrels in the Somatosensory Cortex of Monoamine Oxidase A–Deficient Mice: Role of a Serotonin Excess during the Critical Period, 10.1016/s0896-6273(00)80048-3
  15. Persico AM, J Neurosci, 21, 6862 (2001)
  16. Riccio O, Potter G, Walzer C, Vallet P, Szabó G, Vutskits L, Kiss J Z, Dayer A G, Excess of serotonin affects embryonic interneuron migration through activation of the serotonin receptor 6, 10.1038/mp.2008.89
  17. Hendricks Timothy J., Fyodorov Dmitry V., Wegman Lauren J., Lelutiu Nadia B., Pehek Elizabeth A., Yamamoto Bryan, Silver Jerry, Weeber Edwin J., Sweatt J.David, Deneris Evan S., Pet-1 ETS Gene Plays a Critical Role in 5-HT Neuron Development and Is Required for Normal Anxiety-like and Aggressive Behavior, 10.1016/s0896-6273(02)01167-4
  18. Hodges M. R., Tattersall G. J., Harris M. B., McEvoy S. D., Richerson D. N., Deneris E. S., Johnson R. L., Chen Z.-F., Richerson G. B., Defects in Breathing and Thermoregulation in Mice with Near-Complete Absence of Central Serotonin Neurons, 10.1523/jneurosci.4729-07.2008
  19. Alenina N., Kikic D., Todiras M., Mosienko V., Qadri F., Plehm R., Boye P., Vilianovitch L., Sohr R., Tenner K., Hortnagl H., Bader M., Growth retardation and altered autonomic control in mice lacking brain serotonin, 10.1073/pnas.0810793106
  20. Gutknecht Lise, Waider Jonas, Kraft Stefanie, Kriegebaum Claudia, Holtmann Bettina, Reif Andreas, Schmitt Angelika, Lesch Klaus-Peter, Deficiency of brain 5-HT synthesis but serotonergic neuron formation in Tph2 knockout mice, 10.1007/s00702-008-0096-6
  21. Migliarini S, Fundam Clin Pharmacol, 22, 129 (2008)
  22. Savelieva Katerina V., Zhao Shulei, Pogorelov Vladimir M., Rajan Indrani, Yang Qi, Cullinan Emily, Lanthorn Thomas H., Genetic Disruption of Both Tryptophan Hydroxylase Genes Dramatically Reduces Serotonin and Affects Behavior in Models Sensitive to Antidepressants, 10.1371/journal.pone.0003301
  23. Yadav Vijay K., Oury Franck, Suda Nina, Liu Zhong-Wu, Gao Xiao-Bing, Confavreux Cyrille, Klemenhagen Kristen C., Tanaka Kenji F., Gingrich Jay A., Guo X. Edward, Tecott Laurence H., Mann J. John, Hen Rene, Horvath Tamas L., Karsenty Gerard, A Serotonin-Dependent Mechanism Explains the Leptin Regulation of Bone Mass, Appetite, and Energy Expenditure, 10.1016/j.cell.2009.06.051
  24. Nichols J, Development, 110, 1341 (1990)
  25. Lee E-Chiang, Yu Daiguan, Martinez de Velasco J., Tessarollo Lino, Swing Deborah A., Court Donald L., Jenkins Nancy A., Copeland Neal G., A Highly Efficient Escherichia coli-Based Chromosome Engineering System Adapted for Recombinogenic Targeting and Subcloning of BAC DNA, 10.1006/geno.2000.6451
  26. Ren Shu-Yue, Pasqualetti Massimo, Dierich Andr�e, Le Meur Marianne, Rijli Filippo M., AHoxa2 mutant conditional allele generated by Flp- and Cre-mediated recombination, 10.1002/gene.10052
  27. Dymecki Susan M., Rodríguez Carolyn I., Buchholz Frank, Galloway Jenna, Sequerra Reynaldo, Kasper Jocelyn, Ayala Ramses, Stewart A. Francis, 10.1038/75973
  28. Uyama Osamu, Okamura Nobutaka, Yanase Masahiro, Narita Mitsuhiro, Kawabata Keita, Sugita Minoru, Quantitative Evaluation of Vascular Permeability in the Gerbil Brain after Transient Ischemia Using Evans Blue Fluorescence, 10.1038/jcbfm.1988.59
  29. Pasqualetti Massimo, Nardi Irma, Ladinsky Herbert, Marazziti Donatella, Cassano Giovanni B., Comparative anatomical distribution of serotonin 1A, 1Dα and 2A receptor mRNAs in human brain postmorten, 10.1016/0169-328x(96)00026-5
  30. Pasqualetti Massimo, Neun Rüdiger, Davenne Marc, Rijli Filippo M., 10.1038/ng702
  31. Pasqualetti Massimo, Ren Shu-Yue, Poulet Martine, LeMeur Marianne, Dierich Andr�e, Rijli Filippo M., AHoxa2 knockin allele that expresses EGFP upon conditional Cre-mediated recombination, 10.1002/gene.10053
  32. KEITH N. M., A METHOD FOR THE DETERMINATION OF PLASMA AND BLOOD VOLUME, 10.1001/archinte.1915.00080040043004
  33. De Vitry F., Hamon M., Catelon J., Dubois M., Thibault J., Serotonin initiates and autoamplifies its own synthesis during mouse central nervous system development., 10.1073/pnas.83.22.8629
  34. Galter Dagmar, Unsicker Klaus, Sequential Activation of the 5-HT1A Serotonin Receptor and TrkB Induces the Serotonergic Neuronal Phenotype, 10.1006/mcne.2000.0841
  35. Whitaker-Azmitia Patricia M., Azmitia Efrain C., Stimulation of astroglial serotonin receptors produces culture media which regulates growth of serotonergic neurons, 10.1016/0006-8993(89)90972-4
  36. Lyons W. E., Mamounas L. A., Ricaurte G. A., Coppola V., Reid S. W., Bora S. H., Wihler C., Koliatsos V. E., Tessarollo L., Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities, 10.1073/pnas.96.26.15239
  37. Mamounas LA, J Neurosci, 20, 771 (2000)
  38. Mamounas LA, J Neurosci, 15, 7929 (1995)
  39. Audero E., Coppi E., Mlinar B., Rossetti T., Caprioli A., Banchaabouchi M. A., Corradetti R., Gross C., Sporadic Autonomic Dysregulation and Death Associated with Excessive Serotonin Autoinhibition, 10.1126/science.1157871
  40. Budnik V, J Neurosci, 9, 2866 (1989)
  41. Daubert Elizabeth A., Condron Barry G., Serotonin: a regulator of neuronal morphology and circuitry, 10.1016/j.tins.2010.05.005
  42. Diefenbach Thomas J., Sloley B.Duff, Goldberg Jeffrey I., Neurite Branch Development of an Identified Serotonergic Neuron from Embryonic Helisoma: Evidence for Autoregulation by Serotonin, 10.1006/dbio.1995.1023
  43. Haydon P., McCobb D., Kater S., Serotonin selectively inhibits growth cone motility and synaptogenesis of specific identified neurons, 10.1126/science.6093252
  44. Sikich Linmarie, Hickok Janice M., Todd Richard D., 5-HT1A receptors control neurite branching during development, 10.1016/0165-3806(90)90092-d
  45. Ase Ariel R., Reader Tomás A., Hen René, Riad Mustapha, Descarries Laurent, Regional changes in density of serotonin transporter in the brain of 5-HT1Aand 5-HT1Bknockout mice, and of serotonin innervation in the 5-HT1Bknockout : 5-HT1Aand 5-HT1Bknockout mice, 10.1046/j.1471-4159.2001.00437.x
  46. Dudok Jacobus J., Groffen Alexander J.A., Witter Menno P., Voorn Pieter, Verhage Matthijs, Chronic activation of the 5-HT2 receptor reduces 5-HT neurite density as studied in organotypic slice cultures, 10.1016/j.brainres.2009.08.071
  47. Hannon Jason, Hoyer Daniel, Molecular biology of 5-HT receptors, 10.1016/j.bbr.2008.03.020
  48. Bonnin A., Peng W., Hewlett W., Levitt P., Expression mapping of 5-HT1 serotonin receptor subtypes during fetal and early postnatal mouse forebrain development, 10.1016/j.neuroscience.2006.04.036
  49. Lauder Jean M, Wilkie Mary Beth, Wu Chun, Singh Sujay, Expression of 5-HT2A, 5-HT2B and 5-HT2C receptors in the mouse embryo, 10.1016/s0736-5748(00)00032-0
  50. Lein Ed S., Hawrylycz Michael J., Ao Nancy, Ayres Mikael, Bensinger Amy, Bernard Amy, Boe Andrew F., Boguski Mark S., Brockway Kevin S., Byrnes Emi J., Chen Lin, Chen Li, Chen Tsuey-Ming, Chi Chin Mei, Chong Jimmy, Crook Brian E., Czaplinska Aneta, Dang Chinh N., Datta Suvro, Dee Nick R., Desaki Aimee L., Desta Tsega, Diep Ellen, Dolbeare Tim A., Donelan Matthew J., Dong Hong-Wei, Dougherty Jennifer G., Duncan Ben J., Ebbert Amanda J., Eichele Gregor, Estin Lili K., Faber Casey, Facer Benjamin A., Fields Rick, Fischer Shanna R., Fliss Tim P., Frensley Cliff, Gates Sabrina N., Glattfelder Katie J., Halverson Kevin R., Hart Matthew R., Hohmann John G., Howell Maureen P., Jeung Darren P., Johnson Rebecca A., Karr Patrick T., Kawal Reena, Kidney Jolene M., Knapik Rachel H., Kuan Chihchau L., Lake James H., Laramee Annabel R., Larsen Kirk D., Lau Christopher, Lemon Tracy A., Liang Agnes J., Liu Ying, Luong Lon T., Michaels Jesse, Morgan Judith J., Morgan Rebecca J., Mortrud Marty T., Mosqueda Nerick F., Ng Lydia L., Ng Randy, Orta Geralyn J., Overly Caroline C., Pak Tu H., Parry Sheana E., Pathak Sayan D., Pearson Owen C., Puchalski Ralph B., Riley Zackery L., Rockett Hannah R., Rowland Stephen A., Royall Joshua J., Ruiz Marcos J., Sarno Nadia R., Schaffnit Katherine, Shapovalova Nadiya V., Sivisay Taz, Slaughterbeck Clifford R., Smith Simon C., Smith Kimberly A., Smith Bryan I., Sodt Andy J., Stewart Nick N., Stumpf Kenda-Ruth, Sunkin Susan M., Sutram Madhavi, Tam Angelene, Teemer Carey D., Thaller Christina, Thompson Carol L., Varnam Lee R., Visel Axel, Whitlock Ray M., Wohnoutka Paul E., Wolkey Crissa K., Wong Victoria Y., Wood Matthew, Yaylaoglu Murat B., Young Rob C., Youngstrom Brian L., Feng Yuan Xu, Zhang Bin, Zwingman Theresa A., Jones Allan R., Genome-wide atlas of gene expression in the adult mouse brain, 10.1038/nature05453
  51. Sze Ji Ying, Victor Martin, Loer Curtis, Shi Yang, Ruvkun Gary, Food and metabolic signalling defects in a Caenorhabditis elegans serotonin-synthesis mutant, 10.1038/35000609
  52. Valles AM, J Neurosci, 6, 1482 (1986)
  53. Hill Rachel A., Murray Simon S., Halley Paul G., Binder Michele D., Martin Sally J., van den Buuse Maarten, Brain-derived neurotrophic factor expression is increased in the hippocampus of 5-HT2C receptor knockout mice, 10.1002/hipo.20759
Bibliographic reference Migliarini, S. ; Pacini, G. ; Pelosi, Barbara ; Lunardi, G. ; Pasqualetti, M.. Lack of brain serotonin affects postnatal development and serotonergic neuronal circuitry formation.. In: Molecular Psychiatry, Vol. 18, no.10, p. 1106-1118 (2012)
Permanent URL http://hdl.handle.net/2078/171289