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Autism pp 111–132Cite as

Serotonin Dysfunction in Autism

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Part of the book series: Current Clinical Neurology ((CCNEU))

Abstract

This chapter reviews the evidence for the involvement of the neurotransmitter serotonin in the etiology of autism. Serotonin-containing neurons in the raphe nuclei of the brainstem are among the first neurons to be generated, and their axonal projections extend to widespread areas throughout the brain and spinal cord. Thus, the serotonergic system can influence early developmental events throughout the brain. Other evidence is the generally higher level of serotonin in the blood of patients with autism. In the brain of young children with autism, however, serotonin synthesis is decreased compared to that in normal siblings. Pharmacological studies show symptomatic improvement with agents that enhance serotonergic function and exacerbation of behaviors with drugs that decrease serotonin. Genetic analyses show mutations in the serotonin transporter in autism. Animal models that mimic the changes in serotonin show behavioral, structural and biochemical features that resemble autism. Conversely, models based on other features of autism often show changes in serotonergic markers. The role serotonin exerts in autism is likely through its interactions with other transmitter systems, neurotrophic and growth factors, and immunological factors. Taking all the studies together, the evidence suggests that serotonin is a critical player in the development of the autism phenotype.

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References

  1. Wallace J. A., Lauder J. M. (1983) Development of the serotonergic system in the rat embryo: an immunocytochemical study. Brain Res Bull 10, 459–479.

    PubMed  CAS  Google Scholar 

  2. Wallace J. A., Petrusz P., Lauder J. M. (1982) Serotonin immunocytochemistry in the adult and developing rat brain: methodological and pharmacological considerations. Brain Res Bull 9, 117–129.

    PubMed  CAS  Google Scholar 

  3. Lidov H. G., Molliver M. E. (1982) Immunohistochemical study of the development of serotonergic neurons in the rat CNS. Brain Res Bull 9, 559–604.

    PubMed  CAS  Google Scholar 

  4. Lidov H. G., Molliver M. E. (1982) An immunohistochemical study of serotonin neuron development in the rat: ascending pathways and terminal fields. Brain Res Bull 8, 389–430.

    PubMed  CAS  Google Scholar 

  5. Rubenstein J. L. (1998) Development of serotonergic neurons and their projections. Biol Psychiatry 44, 145–150.

    PubMed  CAS  Google Scholar 

  6. Lauder J. M., Wallace J. A., Krebs H. (1981) Roles for serotonin in neuroembryogenesis. Adv Exp Med Biol 133, 477–506.

    PubMed  CAS  Google Scholar 

  7. Hunt P. N., Gust J., Mccabe A. K., Bosma M. M. (2006) Primary role of the serotonergic midline system in synchronized spontaneous activity during development of the embryonic mouse hindbrain. J Neurobiol 66, 1239–1252.

    PubMed  CAS  Google Scholar 

  8. Laurent A., Goaillard J. M., Cases O., Lebrand C., Gaspar P., Ropert N. (2002) Activity-dependent presynaptic effect of serotonin 1B receptors on the somatosensory thalamocortical transmission in neonatal mice. J Neurosci 22, 886–900.

    PubMed  CAS  Google Scholar 

  9. Beique J. C., Chapin-Penick E. M., Mladenovic L., Andrade R. (2004) Serotonergic facilitation of synaptic activity in the developing rat prefrontal cortex. J Physiol 556, 739–754.

    PubMed  CAS  Google Scholar 

  10. Pardo C. A., Eberhart C. G. (2007) The neurobiology of autism. Brain Pathol 17, 434–447.

    PubMed  CAS  Google Scholar 

  11. Aghajanian G. K., Marek G. J. (1999) Serotonin, via 5-HT2A receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release. Brain Res 825, 161–171.

    PubMed  CAS  Google Scholar 

  12. Aghajanian G. K., Marek G. J. (1997) Serotonin induces excitatory postsynaptic potentials in apical dendrites of neocortical pyramidal cells. Neuropharmacology 36, 589–599.

    PubMed  CAS  Google Scholar 

  13. Marek G. J., Wright R. A., Schoepp D. D. (2006) 5-Hydroxytryptamine2A (5-HT2A) receptor regulation in rat prefrontal cortex: interaction of a phenethylamine hallucinogen and the metabotropic glutamate2/3 receptor agonist LY354740. Neurosci Lett 403, 256–260.

    PubMed  CAS  Google Scholar 

  14. Kalia M. (2005) Neurobiological basis of depression: an update. Metabolism 54, 24–27.

    PubMed  CAS  Google Scholar 

  15. Gallinat J., Strohle A., Lang U. E., et al. (2005) Association of human hippocampal neurochemistry, serotonin transporter genetic variation, and anxiety. Neuroimage 26, 123–131.

    PubMed  Google Scholar 

  16. Aghajanian G. K., Marek G. J. (2000) Serotonin model of schizophrenia: emerging role of glutamate mechanisms. Brain Res Brain Res Rev 31, 302–312.

    PubMed  CAS  Google Scholar 

  17. Aghajanian G. K., Marek G. J. (1999) Serotonin and hallucinogens. Neuropsychopharmacology 21, 16S–23S.

    PubMed  CAS  Google Scholar 

  18. Marek G. J. (2007) Serotonin and dopamine interactions in rodents and primates: implications for psychosis and antipsychotic drug development. Int Rev Neurobiol 78, 165–192.

    PubMed  CAS  Google Scholar 

  19. Kolevzon A., Mathewson K. A., Hollander E. (2006) Selective serotonin reuptake inhibitors in autism: a review of efficacy and tolerability. J Clin Psychiatry 67, 407–414.

    PubMed  CAS  Google Scholar 

  20. Pae C. U., Patkar A. A. (2007) Paroxetine: current status in psychiatry. Expert Rev Neurother 7, 107–120.

    PubMed  CAS  Google Scholar 

  21. Carrasco J. L., Sandner C. (2005) Clinical effects of pharmacological variations in selective serotonin reuptake inhibitors: an overview. Int J Clin Pract 59, 1428–1434.

    PubMed  CAS  Google Scholar 

  22. Arroll B., Macgillivray S., Ogston S., et al. (2005) Efficacy and tolerability of tricyclic antidepressants and SSRIs compared with placebo for treatment of depression in primary care: a meta-analysis. Ann Fam Med 3, 449–456.

    PubMed  Google Scholar 

  23. Keller M. B. (2000) Citalopram therapy for depression: a review of 10 years of European experience and data from U.S. clinical trials. J Clin Psychiatry 61, 896–908.

    PubMed  CAS  Google Scholar 

  24. Bezchlibnyk-Butler K., Aleksic I., Kennedy S. H. (2000) Citalopram--a review of pharmacological and clinical effects. J Psychiatry Neurosci 25, 241–254.

    PubMed  CAS  Google Scholar 

  25. Geddes J. R., Freemantle N., Mason J., Eccles M. P., Boynton J. (2000) SSRIs versus other antidepressants for depressive disorder. Cochrane Database Syst Rev CD001851 (2).

    Google Scholar 

  26. Devane C. L., Sallee F. R. (1996) Serotonin selective reuptake inhibitors in child and adolescent psychopharmacology: a review of published experience. J Clin Psychiatry 57, 55–66.

    PubMed  CAS  Google Scholar 

  27. Hetrick S., Merry S., Mckenzie J., Sindahl P., Proctor M. (2007) Selective serotonin reuptake inhibitors (SSRIs) for depressive disorders in children and adolescents. Cochrane Database Syst Rev CD004851 (3).

    Google Scholar 

  28. Farley R. L. (2005) Pharmacological treatment of major depressive disorder in adolescents. ScientificWorldJournal 5, 420–426.

    PubMed  CAS  Google Scholar 

  29. Weller E. B., Tucker S., Weller R. A. (2005) The selective serotonin reuptake inhibitors controversy in the treatment of depression in children. Curr Psychiatry Rep 7, 87–90.

    PubMed  Google Scholar 

  30. Courtney D. B. (2004) Selective serotonin reuptake inhibitor and venlafaxine use in children and adolescents with major depressive disorder: a systematic review of published randomized controlled trials. Can J Psychiatry 49, 557–563.

    PubMed  Google Scholar 

  31. Moore M. L., Eichner S. F., Jones J. R. (2004) Treating functional impairment of autism with selective serotonin-reuptake inhibitors. Ann Pharmacother 38, 1515–1519.

    PubMed  CAS  Google Scholar 

  32. Posey D. J., Erickson C. A., Stigler K. A., Mcdougle C. J. (2006) The use of selective serotonin reuptake inhibitors in autism and related disorders. J Child Adolesc Psychopharmacol 16, 181–186.

    PubMed  Google Scholar 

  33. Baghdadli A., Gonnier V., Aussilloux C. (2002) [Review of psychopharmacological treatments in adolescents and adults with autistic disorders]. Encephale 28, 248–254.

    PubMed  CAS  Google Scholar 

  34. Buchsbaum M. S., Hollander E., Haznedar M. M., et al. (2001) Effect of fluoxetine on regional cerebral metabolism in autistic spectrum disorders: a pilot study. Int J Neuropsychopharmacol 4, 119–125.

    PubMed  CAS  Google Scholar 

  35. Delong G. R., Teague L. A., Mcswain Kamran M. (1998) Effects of fluoxetine treatment in young children with idiopathic autism. Dev Med Child Neurol 40, 551–562.

    PubMed  CAS  Google Scholar 

  36. Fatemi S. H., Realmuto G. M., Khan L., Thuras P. (1998) Fluoxetine in treatment of adolescent patients with autism: a longitudinal open trial. J Autism Dev Disord 28, 303–307.

    PubMed  CAS  Google Scholar 

  37. Ghaziuddin M., Tsai L., Ghaziuddin N. (1991) Fluoxetine in autism with depression. J Am Acad Child Adolesc Psychiatry 30, 508–509.

    PubMed  CAS  Google Scholar 

  38. Schain R., Freedman D. (1961) Studies on 5-hydroxyindole metablism in autistic and other mentally retarded children. J Pediatr 58, 315–320.

    PubMed  CAS  Google Scholar 

  39. Cook E. H. (1990) Autism: review of neurochemical investigation. Synapse 6, 292–308.

    PubMed  CAS  Google Scholar 

  40. Burgess N. K., Sweeten T. L., Mcmahon W. M., Fujinami R. S. (2006) Hyperserotoninemia and altered immunity in autism. J Autism Dev Disord 36, 697–704.

    PubMed  Google Scholar 

  41. Lam K. S., Aman M. G., Arnold L. E. (2006) Neurochemical correlates of autistic disorder: a review of the literature. Res Dev Disabil 27, 254–289.

    PubMed  Google Scholar 

  42. Cook E. H., Leventhal B. L. (1996) The serotonin system in autism. Curr Opin Pediatr 8, 348–354.

    PubMed  CAS  Google Scholar 

  43. D’eufemia P., Finocchiaro R., Celli M., Viozzi L., Monteleone D., Giardini O. (1995) Low serum tryptophan to large neutral amino acids ratio in idiopathic infantile autism. Biomed Pharmacother 49, 288–292.

    PubMed  Google Scholar 

  44. Buitelaar J. K., Willemsen-Swinkels S. H. (2000) Autism: current theories regarding its pathogenesis and implications for rational pharmacotherapy. Paediatr Drugs 2, 67–81.

    PubMed  CAS  Google Scholar 

  45. Klauck S. M., Poustka F., Benner A., Lesch K. P., Poustka A. (1997) Serotonin transporter (5-HTT) gene variants associated with autism? Hum Mol Genet 6, 2233–2238.

    PubMed  CAS  Google Scholar 

  46. Connors S. L., Matteson K. J., Sega G. A., Lozzio C. B., Carroll R. C., Zimmerman A. W. (2006) Plasma serotonin in autism. Pediatr Neurol 35, 182–186.

    PubMed  Google Scholar 

  47. Cote F., Fligny C., Bayard E., et al. (2007) Maternal serotonin is crucial for murine embryonic development. Proc Natl Acad Sci U S A 104, 329–334.

    PubMed  CAS  Google Scholar 

  48. Whitaker-Azmitia P. M. (2005) Behavioral and cellular consequences of increasing serotonergic activity during brain development: a role in autism? Int J Dev Neurosci 23, 75–83.

    PubMed  CAS  Google Scholar 

  49. Mcbride P. A., Anderson G. M., Hertzig M. E., et al. (1998) Effects of diagnosis, race, and puberty on platelet serotonin levels in autism and mental retardation. J Am Acad Child Adolesc Psychiatry 37, 767–776.

    PubMed  CAS  Google Scholar 

  50. Cook E. H., Jr., Arora R. C., Anderson G. M., et al. (1993) Platelet serotonin studies in hyperserotonemic relatives of children with autistic disorder. Life Sci 52, 2005–2015.

    PubMed  Google Scholar 

  51. Murphy D. G., Daly E., Schmitz N., et al. (2006) Cortical serotonin 5-HT2A receptor binding and social communication in adults with Asperger’s syndrome: an in vivo SPECT study. Am J Psychiatry 163, 934–936.

    PubMed  Google Scholar 

  52. Buitelaar J. K., Willemsen-Swinkels S. H. (2000) Medication treatment in subjects with autistic spectrum disorders. Eur Child Adolesc Psychiatry 9, 185–197.

    Google Scholar 

  53. Mcdougle C. J., Scahill L., Mccracken J. T., et al. (2000) Research Units on Pediatric Psychopharmacology (RUPP) Autism Network. Background and rationale for an initial controlled study of risperidone. Child Adolesc Psychiatr Clin N Am 9, 201–224.

    PubMed  CAS  Google Scholar 

  54. Cook E. H., Jr., Courchesne R., Lord C., et al. (1997) Evidence of linkage between the serotonin transporter and autistic disorder. Mol Psychiatry 2, 247–250.

    PubMed  Google Scholar 

  55. Devlin B., Cook E. H., Jr., Coon H., et al. (2005) Autism and the serotonin transporter: the long and short of it. Mol Psychiatry 10, 1110–1116.

    PubMed  CAS  Google Scholar 

  56. Sutcliffe J. S., Delahanty R. J., Prasad H. C., 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.

    PubMed  CAS  Google Scholar 

  57. Hu V. W., Frank B. C., Heine S., Lee N. H., Quackenbush J. (2006) Gene expression profiling of lymphoblastoid cell lines from monozygotic twins discordant in severity of autism reveals differential regulation of neurologically relevant genes. BMC Genomics 7, 118.

    PubMed  Google Scholar 

  58. Seckl J. R., Meaney M. J. (2004) Glucocorticoid programming. Ann N Y Acad Sci 1032, 63–84.

    PubMed  CAS  Google Scholar 

  59. Vazquez D. M., Lopez J. F., Van Hoers H., Watson S. J., Levine S. (2000) Maternal deprivation regulates serotonin 1A and 2A receptors in the infant rat. Brain Res 855, 76–82.

    PubMed  CAS  Google Scholar 

  60. Weaver I. C., Diorio J., Seckl J. R., Szyf M., Meaney M. J. (2004) Early environmental regulation of hippocampal glucocorticoid receptor gene expression: characterization of intracellular mediators and potential genomic target sites. Ann N Y Acad Sci 1024, 182–212.

    PubMed  CAS  Google Scholar 

  61. Corbett B. A., Mendoza S., Abdullah M., Wegelin J. A., Levine S. (2006) Cortisol circadian rhythms and response to stress in children with autism. Psychoneuroendocrinology 31, 59–68.

    PubMed  CAS  Google Scholar 

  62. Jansen L. M., Gispen-De Wied C. C., Wiegant V. M., Westenberg H. G., Lahuis B. E., Van Engeland H. (2006) Autonomic and neuroendocrine responses to a psychosocial stressor in adults with autistic spectrum disorder. J Autism Dev Disord 36, 891–899.

    PubMed  Google Scholar 

  63. Hazell P. (2007) Drug therapy for attention-deficit/hyperactivity disorder-like symptoms in autistic disorder. J Paediatr Child Health 43, 19–24.

    PubMed  Google Scholar 

  64. Hollander E., Phillips A., Chaplin W., et al. (2005) A placebo controlled crossover trial of liquid fluoxetine on repetitive behaviors in childhood and adolescent autism. Neuropsychopharmacology 30, 582–589.

    PubMed  CAS  Google Scholar 

  65. Cook E. H., Jr., Rowlett R., Jaselskis C., Leventhal B. L. (1992) Fluoxetine treatment of children and adults with autistic disorder and mental retardation. J Am Acad Child Adolesc Psychiatry 31, 739–745.

    PubMed  Google Scholar 

  66. Mcdougle C. J., Naylor S. T., Cohen D. J., Aghajanian G. K., Heninger G. R., Price L. H. (1996) Effects of tryptophan depletion in drug-free adults with autistic disorder. Arch Gen Psychiatry 53, 993–1000.

    PubMed  CAS  Google Scholar 

  67. Chugani D. C., Muzik O., Behen M., et al. (1999) Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children. Ann Neurol 45, 287–295.

    PubMed  CAS  Google Scholar 

  68. Chugani D. C., Muzik O., Rothermel R., et al. (1997) Altered serotonin synthesis in the dentatothalamocortical pathway in autistic boys. Ann Neurol 42, 666–669.

    PubMed  CAS  Google Scholar 

  69. Chandana S. R., Behen M. E., Juhasz C., et al. (2005) Significance of abnormalities in developmental trajectory and asymmetry of cortical serotonin synthesis in autism. Int J Dev Neurosci 23, 171–182.

    PubMed  CAS  Google Scholar 

  70. Wassink T. H., Hazlett H. C., Epping E. A., et al. (2007) Cerebral cortical gray matter overgrowth and functional variation of the serotonin transporter gene in autism. Arch Gen Psychiatry 64, 709–717.

    PubMed  CAS  Google Scholar 

  71. Hohmann C. F., Hamon R., Batshaw M. L., Coyle J. T. (1988) Transient postnatal elevation of serotonin levels in mouse neocortex. Brain Res 471, 163–166.

    PubMed  CAS  Google Scholar 

  72. Connell S., Karikari C., Hohmann C. F. (2004) Sex-specific development of cortical monoamine levels in mouse. Brain Res Dev Brain Res 151, 187–191.

    PubMed  CAS  Google Scholar 

  73. Fujimiya M., Hosoda S., Kitahama K., Kimura H., Maeda T. (1986) Early development of serotonin neuron in the rat brain as studied by immunohistochemistry combined with tryptophan administration. Brain Dev 8, 335–342.

    PubMed  CAS  Google Scholar 

  74. D’amato R. J., Blue M. E., Largent B. L., et al. (1987) Ontogeny of the serotonergic projection to rat neocortex: transient expression of a dense innervation to primary sensory areas. Proc Natl Acad Sci U S A 84, 4322–4326.

    PubMed  Google Scholar 

  75. Rhoades R. W., Bennett-Clarke C. A., Chiaia N. L., et al. (1990) Development and lesion induced reorganization of the cortical representation of the rat’s body surface as revealed by immunocytochemistry for serotonin. J Comp Neurol 293, 190–207.

    PubMed  CAS  Google Scholar 

  76. Blue M. E., Erzurumlu R. S., Jhaveri S. (1991) A comparison of pattern formation by thalamocortical and serotonergic afferents in the rat barrel field cortex. Cereb Cortex 1, 380–389.

    PubMed  CAS  Google Scholar 

  77. Woolsey T. A., Van Der Loos H. (1970) The structural organization of layer IV in the somatosensory region (SI) of mouse cerebral cortex. The description of a cortical field composed of discrete cytoarchitectonic units. Brain Res 17, 205–242.

    PubMed  CAS  Google Scholar 

  78. Bennett-Clarke C. A., Chiaia N. L., Rhoades R. W. (1996) Thalamocortical afferents in rat transiently express high-affinity serotonin uptake sites. Brain Res 733, 301–306.

    PubMed  CAS  Google Scholar 

  79. Bennett-Clarke C. A., Lane R. D., Rhoades R. W. (1995) Fenfluramine depletes serotonin from the developing cortex and alters thalamocortical organization. Brain Res 702, 255–260.

    PubMed  CAS  Google Scholar 

  80. Bennett-Clarke C. A., Leslie M. J., Chiaia N. L., Rhoades R. W. (1993) Serotonin 1B receptors in the developing somatosensory and visual cortices are located on thalamocortical axons. Proc Natl Acad Sci U S A 90, 153–157.

    PubMed  CAS  Google Scholar 

  81. Cases O., Lebrand C., Giros B., et al. (1998) Plasma membrane transporters of serotonin, dopamine, and norepinephrine mediate serotonin accumulation in atypical locations in the developing brain of monoamine oxidase A knock-outs. J Neurosci 18, 6914–6927.

    PubMed  CAS  Google Scholar 

  82. Lebrand C., Cases O., Adelbrecht C., et al. (1996) Transient uptake and storage of serotonin in developing thalamic neurons. Neuron 17, 823–835.

    PubMed  CAS  Google Scholar 

  83. Lebrand C., Cases O., Wehrle R., Blakely R. D., Edwards R. H., Gaspar P. (1998) Transient developmental expression of monoamine transporters in the rodent forebrain. J Comp Neurol 401, 506–524.

    PubMed  CAS  Google Scholar 

  84. Mansour-Robaey S., Mechawar N., Radja F., Beaulieu C., Descarries L. (1998) Quantified distribution of serotonin transporter and receptors during the postnatal development of the rat barrel field cortex. Brain Res Dev Brain Res 107, 159–163.

    PubMed  CAS  Google Scholar 

  85. Rhoades R. W., Bennett-Clarke C. A., Shi M. Y., Mooney R. D. (1994) Effects of 5-HT on thalamocortical synaptic transmission in the developing rat. J Neurophysiol 72, 2438–2450.

    PubMed  CAS  Google Scholar 

  86. Lieske V., Bennett-Clarke C. A., Rhoades R. W. (1999) Effects of serotonin on neurite outgrowth from thalamic neurons in vitro. Neuroscience 90, 967–974.

    PubMed  CAS  Google Scholar 

  87. Lotto B., Upton L., Price D. J., Gaspar P. (1999) Serotonin receptor activation enhances neurite outgrowth of thalamic neurones in rodents. Neurosci Lett 269, 87–90.

    PubMed  CAS  Google Scholar 

  88. Dooley A. E., Pappas I. S., Parnavelas J. G. (1997) Serotonin promotes the survival of cortical glutamatergic neurons in vitro. Exp Neurol 148, 205–214.

    PubMed  CAS  Google Scholar 

  89. Lavdas A. A., Blue M. E., Lincoln J., Parnavelas J. G. (1997) Serotonin promotes the differentiation of glutamate neurons in organotypic slice cultures of the developing cerebral cortex. J Neurosci 17, 7872–7880.

    PubMed  CAS  Google Scholar 

  90. Osterheld-Haas M. C., Hornung J. P. (1996) Laminar development of the mouse barrel cortex: effects of neurotoxins against monoamines. Exp Brain Res 110, 183–195.

    PubMed  CAS  Google Scholar 

  91. Bennett-Clarke C. A., Leslie M. J., Lane R. D., Rhoades R. W. (1994) Effect of serotonin depletion on vibrissa-related patterns of thalamic afferents in the rat’s somatosensory cortex. J Neurosci 14, 7594–7607.

    PubMed  CAS  Google Scholar 

  92. Persico A. M., Altamura C., Calia E., et al. (2000) Serotonin depletion and barrel cortex development: impact of growth impairment vs. serotonin effects on thalamocortical endings. Cereb Cortex 10, 181–191.

    PubMed  CAS  Google Scholar 

  93. Vitalis T., Cases O., Callebert J., et al. (1998) Effects of monoamine oxidase A inhibition on barrel formation in the mouse somatosensory cortex: determination of a sensitive developmental period. J Comp Neurol 393, 169–184.

    PubMed  CAS  Google Scholar 

  94. Persico A. M., Mengual E., Moessner R., et al. (2001) Barrel pattern formation requires serotonin uptake by thalamocortical afferents, and not vesicular monoamine release. J Neurosci 21, 6862–6873.

    PubMed  CAS  Google Scholar 

  95. Mazer C., Muneyyirci J., Taheny K., Raio N., Borella A., Whitaker-Azmitia P. (1997) Serotonin depletion during synaptogenesis leads to decreased synaptic density and learning deficits in the adult rat: a possible model of neurodevelopmental disorders with cognitive deficits. Brain Res 760, 68–73.

    PubMed  CAS  Google Scholar 

  96. Salichon N., Gaspar P., Upton A. L., et al. (2001) Excessive activation of serotonin (5-HT) 1B receptors disrupts the formation of sensory maps in monoamine oxidase a and 5-ht transporter knock-out mice. J Neurosci 21, 884–896.

    PubMed  CAS  Google Scholar 

  97. Salt T. E., Eaton S. A. (1996) Functions of ionotropic and metabotropic glutamate receptors in sensory transmission in the mammalian thalamus. Prog Neurobiol 48, 55–72.

    PubMed  CAS  Google Scholar 

  98. Constantine-Paton M., Cline H. T., Debski E. (1990) Patterned activity, synaptic convergence, and the NMDA receptor in developing visual pathways. Annu Rev Neurosci 13, 129–154.

    PubMed  CAS  Google Scholar 

  99. Fox K., Daw N. W. (1993) Do NMDA receptors have a critical function in visual cortical plasticity? Trends Neurosci 16, 116–122.

    PubMed  CAS  Google Scholar 

  100. Hattori H., Wasterlain C. G. (1990) Excitatory amino acids in the developing brain: ontogeny, plasticity, and excitotoxicity. Pediatr Neurol 6, 219–228.

    PubMed  CAS  Google Scholar 

  101. Mcdonald J. W., Johnston M. V. (1990) Physiological and pathophysiological roles of excitatory amino acids during central nervous system development. Brain Res Brain Res Rev 15, 41–70.

    PubMed  Google Scholar 

  102. Pin J. P., Duvoisin R. (1995) The metabotropic glutamate receptors: structure and functions. Neuropharmacology 34, 1–26.

    PubMed  CAS  Google Scholar 

  103. Bear M. F., Colman H. (1990) Binocular competition in the control of geniculate cell size depends upon visual cortical N-methyl-D-aspartate receptor activation. Proc Natl Acad Sci U S A 87, 9246–9249.

    PubMed  CAS  Google Scholar 

  104. Cline H. T., Constantine-Paton M. (1989) NMDA receptor antagonists disrupt the retinotectal topographic map. Neuron 3, 413–426.

    PubMed  CAS  Google Scholar 

  105. Rocha M., Sur M. (1995) Rapid acquisition of dendritic spines by visual thalamic neurons after blockade of N-methyl-D-aspartate receptors. Proc Natl Acad Sci U S A 92, 8026–8030.

    PubMed  CAS  Google Scholar 

  106. Datwani A., Iwasato T., Itohara S., Erzurumlu R. S. (2002) NMDA receptor-dependent pattern transfer from afferents to postsynaptic cells and dendritic differentiation in the barrel cortex. Mol Cell Neurosci 21, 477–492.

    PubMed  CAS  Google Scholar 

  107. Lee L. J., Iwasato T., Itohara S., Erzurumlu R. S. (2005) Exuberant thalamocortical axon arborization in cortex-specific NMDAR1 knockout mice. J Comp Neurol 485, 280–292.

    PubMed  CAS  Google Scholar 

  108. Iwasato T., Datwani A., Wolf A. M., et al. (2000) Cortex-restricted disruption of NMDAR1 impairs neuronal patterns in the barrel cortex. Nature 406, 726–731.

    PubMed  CAS  Google Scholar 

  109. Iwasato T., Erzurumlu R. S., Huerta P. T., et al. (1997) NMDA receptor-dependent refinement of somatotopic maps. Neuron 19, 1201–1210.

    PubMed  CAS  Google Scholar 

  110. Salt T. E., Turner J. P. (1998a) Modulation of sensory inhibition in the ventrobasal thalamus via activation of group II metabotropic glutamate receptors by 2R,4R- aminopyrrolidine-2,4-dicarboxylate. Exp Brain Res 121, 181–185.

    CAS  Google Scholar 

  111. Salt T. E., Turner J. P. (1998b) Reduction of sensory and metabotropic glutamate receptor responses in the thalamus by the novel metabotropic glutamate receptor-1-selective antagonist S-2-methyl-4-carboxy-phenylglycine. Neuroscience 85, 655–658.

    CAS  Google Scholar 

  112. Mateo Z., Porter J. T. (2007) Group II metabotropic glutamate receptors inhibit glutamate release at thalamocortical synapses in the developing somatosensory cortex. Neuroscience 146, 1062–1072.

    PubMed  CAS  Google Scholar 

  113. Kossut M., Glazewski S., Siucinska E., Skangiel-Kramska J. (1993) Functional plasticity and neurotransmitter receptor binding in the vibrissal barrel cortex. Acta Neurobiol Exp 53, 161–173.

    CAS  Google Scholar 

  114. Bortolotto Z. A., Bashir Z. I., Davies C. H., Collingridge G. L. (1994) A molecular switch activated by metabotropic glutamate receptors regulates induction of long-term potentiation. Nature 368, 740–743.

    PubMed  CAS  Google Scholar 

  115. Shigemoto R., Abe T., Nomura S., Nakanishi S., Hirano T. (1994) Antibodies inactivating mGluR1 metabotropic glutamate receptor block long-term depression in cultured Purkinje cells. Neuron 12, 1245–1255.

    PubMed  CAS  Google Scholar 

  116. O’connor J. J., Rowan M. J., Anwyl R. (1994) Long-lasting enhancement of NMDA receptor-mediated synaptic transmission by metabotropic glutamate receptor activation. Nature 367, 557–559.

    PubMed  Google Scholar 

  117. Dudek S. M. (1996) A discussion of activity-dependent forms of synaptic weakening and their possible role in ocular dominance plasticity. J Physiol Paris 90, 167–170.

    PubMed  CAS  Google Scholar 

  118. Gomperts S. N., Carroll R., Malenka R. C., Nicoll R. A. (2000) Distinct roles for ionotropic and metabotropic glutamate receptors in the maturation of excitatory synapses. J Neurosci 20, 2229–2237.

    PubMed  CAS  Google Scholar 

  119. Hannan A. J., Blakemore C., Katsnelson A., et al. (2001) PLC-beta1, activated via mGluRs, mediates activity-dependent differentiation in cerebral cortex. Nat Neurosci 4, 282–288.

    PubMed  CAS  Google Scholar 

  120. Catania M. V., D’antoni S., Bonaccorso C. M., Aronica E., Bear M. F., Nicoletti F. (2007) Group I metabotropic glutamate receptors: a role in neurodevelopmental disorders? Mol Neurobiol 35, 298–307.

    PubMed  CAS  Google Scholar 

  121. Marty S., Carroll P., Cellerino A., et al. (1996) Brain-derived neurotrophic factor promotes the differentiation of various hippocampal nonpyramidal neurons, including Cajal-Retzius cells, in organotypic slice cultures. J Neurosci 16, 675–687.

    PubMed  CAS  Google Scholar 

  122. Cellerino A., Maffei L. (1996) The action of neurotrophins in the development and plasticity of the visual cortex. Prog Neurobiol 49, 53–71.

    PubMed  CAS  Google Scholar 

  123. Xu B., Gottschalk W., Chow A., et al. (2000) The role of brain-derived neurotrophic factor receptors in the mature hippocampus: modulation of long-term potentiation through a presynaptic mechanism involving TrkB. J Neurosci 20, 6888–6897.

    PubMed  CAS  Google Scholar 

  124. Xu B., Zang K., Ruff N. L., et al. (2000) Cortical degeneration in the absence of neurotrophin signaling: dendritic retraction and neuronal loss after removal of the receptor TrkB. Neuron 26, 233–245.

    PubMed  CAS  Google Scholar 

  125. Reichardt L. F. (2006) Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond B Biol Sci 361, 1545–1564.

    PubMed  CAS  Google Scholar 

  126. Branchi I., Francia N., Alleva E. (2004) Epigenetic control of neurobehavioural plasticity: the role of neurotrophins. Behav Pharmacol 15, 353–362.

    PubMed  CAS  Google Scholar 

  127. Huang E. J., Reichardt L. F. (2003) Trk receptors: roles in neuronal signal transduction. Annu Rev Biochem 72, 609–642.

    PubMed  CAS  Google Scholar 

  128. Mattson M. P., Maudsley S., Martin B. (2004) BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends Neurosci 27, 589–594.

    PubMed  CAS  Google Scholar 

  129. Lyons W. E., Mamounas L. A., Ricaurte G. A., et al. (1999) Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proc Natl Acad Sci U S A 96, 15239–15244.

    PubMed  CAS  Google Scholar 

  130. Daws L. C., Munn J. L., Valdez M. F., Frosto-Burke T., Hensler J. G. (2007) Serotonin transporter function, but not expression, is dependent on brain-derived neurotrophic factor (BDNF): in vivo studies in BDNF-deficient mice. J Neurochem 101, 641–651.

    Google Scholar 

  131. Grider M. H., Mamounas L. A., Le W., Shine H. D. (2005) In situ expression of brain-derived neurotrophic factor or neurotrophin-3 promotes sprouting of cortical serotonergic axons following a neurotoxic lesion. J Neurosci Res 82, 404–412.

    PubMed  CAS  Google Scholar 

  132. Mamounas L. A., Altar C. A., Blue M. E., Kaplan D. R., Tessarollo L., Lyons W. E. (2000) BDNF promotes the regenerative sprouting, but not survival, of injured serotonergic axons in the adult rat brain. J Neurosci 20, 771–782.

    PubMed  CAS  Google Scholar 

  133. Zetterstrom T. S., Pei Q., Madhav T. R., Coppell A. L., Lewis L., Grahame-Smith D. G. (1999) Manipulations of brain 5-HT levels affect gene expression for BDNF in rat brain. Neuropharmacology 38, 1063–1073.

    PubMed  CAS  Google Scholar 

  134. Angelucci F., Mathe A. A., Aloe L. (2004) Neurotrophic factors and CNS disorders: findings in rodent models of depression and schizophrenia. Prog Brain Res 146, 151–165.

    PubMed  CAS  Google Scholar 

  135. Duman R. S. (2004) Role of neurotrophic factors in the etiology and treatment of mood disorders. Neuromolecular Med 5, 11–25.

    PubMed  CAS  Google Scholar 

  136. Shoval G., Weizman A. (2005) The possible role of neurotrophins in the pathogenesis and therapy of schizophrenia. Eur Neuropsychopharmacol 15, 319–329.

    PubMed  CAS  Google Scholar 

  137. Neumeister A., Yuan P., Young T. A., et al. (2005) Effects of tryptophan depletion on serum levels of brain-derived neurotrophic factor in unmedicated patients with remitted depression and healthy subjects. Am J Psychiatry 162, 805–807.

    PubMed  Google Scholar 

  138. Nelson K. B., Grether J. K., Croen L. A., et al. (2001) Neuropeptides and neurotrophins in neonatal blood of children with autism or mental retardation. Ann Neurol 49, 597–606.

    PubMed  CAS  Google Scholar 

  139. Miyazaki K., Narita N., Sakuta R., et al. (2004) Serum neurotrophin concentrations in autism and mental retardation: a pilot study. Brain Dev 26, 292–295.

    PubMed  Google Scholar 

  140. Connolly A. M., Chez M., Streif E. M., et al. (2006) Brain-derived neurotrophic factor and autoantibodies to neural antigens in sera of children with autistic spectrum disorders, Landau-Kleffner syndrome, and epilepsy. Biol Psychiatry 59, 354–363.

    PubMed  CAS  Google Scholar 

  141. Mcallister A. K. (2002) Neurotrophins and cortical development. Results Probl Cell Differ 39, 89–112.

    PubMed  CAS  Google Scholar 

  142. Galter D., Unsicker K. (2000) Brain-derived neurotrophic factor and trkB are essential for cAMP-mediated induction of the serotonergic neuronal phenotype. J Neurosci Res 61, 295–301.

    PubMed  CAS  Google Scholar 

  143. Fryer R. H., Kaplan D. R., Feinstein S. C., Radeke M. J., Grayson D. R., Kromer L. F. (1996) Developmental and mature expression of full-length and truncated TrkB receptors in the rat forebrain. J Comp Neurol 374, 21–40.

    PubMed  CAS  Google Scholar 

  144. Kuipers S. D., Bramham C. R. (2006) Brain-derived neurotrophic factor mechanisms and function in adult synaptic plasticity: new insights and implications for therapy. Curr Opin Drug Discov Devel 9, 580–586.

    PubMed  CAS  Google Scholar 

  145. Gomes R. A., Hampton C., El-Sabeawy F., Sabo S. L., Mcallister A. K. (2006) The dynamic distribution of TrkB receptors before, during, and after synapse formation between cortical neurons. J Neurosci 26, 11487–11500.

    PubMed  CAS  Google Scholar 

  146. Roceri M., Cirulli F., Pessina C., Peretto P., Racagni G., Riva M. A. (2004) Postnatal repeated maternal deprivation produces age-dependent changes of brain-derived neurotrophic factor expression in selected rat brain regions. Biol Psychiatry 55, 708–714.

    PubMed  CAS  Google Scholar 

  147. Fumagalli F., Bedogni F., Perez J., Racagni G., Riva M. A. (2004) Corticostriatal brain-derived neurotrophic factor dysregulation in adult rats following prenatal stress. Eur J Neurosci 20, 1348–1354.

    PubMed  Google Scholar 

  148. Garoflos E., Panagiotaropoulos T., Pondiki S., Stamatakis A., Philippidis E., Stylianopoulou F. (2005) Cellular mechanisms underlying the effects of an early experience on cognitive abilities and affective states. Ann Gen Psychiatry 4, 8.

    PubMed  Google Scholar 

  149. Gilmore J. H., Jarskog L. F., Vadlamudi S. (2003) Maternal infection regulates BDNF and NGF expression in fetal and neonatal brain and maternal-fetal unit of the rat. J Neuroimmunol 138, 49–55.

    PubMed  CAS  Google Scholar 

  150. Cavus I., Duman R. S. (2003) Influence of estradiol, stress, and 5-HT2A agonist treatment on brain-derived neurotrophic factor expression in female rats. Biol Psychiatry 54, 59–69.

    PubMed  CAS  Google Scholar 

  151. Szapacs M. E., Mathews T. A., Tessarollo L., Ernest Lyons W., Mamounas L. A., Andrews A. M. (2004) Exploring the relationship between serotonin and brain-derived neurotrophic factor: analysis of BDNF protein and extraneuronal 5-HT in mice with reduced serotonin transporter or BDNF expression. J Neurosci Methods 140, 81–92.

    PubMed  CAS  Google Scholar 

  152. Vaidya V. A., Terwilliger R. M., Duman R. S. (1999) Role of 5-HT2A receptors in the stress-induced down-regulation of brain- derived neurotrophic factor expression in rat hippocampus. Neurosci Lett 262, 1–4.

    PubMed  CAS  Google Scholar 

  153. Croonenberghs J., Wauters A., Devreese K., et al. (2002) Increased serum albumin, gamma globulin, immunoglobulin IgG, and IgG2 and IgG4 in autism. Psychol Med 32, 1457–1463.

    Google Scholar 

  154. Malek-Ahmadi P. (2001) Cytokines and etiopathogenesis of pervasive developmental disorders. Med Hypotheses 56, 321–324.

    PubMed  CAS  Google Scholar 

  155. Bauer S., Kerr B. J., Patterson P. H. (2007) The neuropoietic cytokine family in development, plasticity, disease and injury. Nat Rev Neurosci 8, 221–232.

    PubMed  CAS  Google Scholar 

  156. Pardo C. A., Vargas D. L., Zimmerman A. W. (2005) Immunity, neuroglia and neuroinflammation in autism. Int Rev Psychiatry 17, 485–495.

    PubMed  Google Scholar 

  157. Korvatska E., Van De Water J., Anders T. F., Gershwin M. E. (2002) Genetic and immunologic considerations in autism. Neurobiol Dis 9, 107–125.

    PubMed  CAS  Google Scholar 

  158. Licinio J., Alvarado I., Wong M. L. (2002) Autoimmunity in autism. Mol Psychiatry 7, 329.

    PubMed  CAS  Google Scholar 

  159. Torrente F., Ashwood P., Day R., et al. (2002) Small intestinal enteropathy with epithelial IgG and complement deposition in children with regressive autism. Mol Psychiatry 7, 375–382, 34.

    PubMed  CAS  Google Scholar 

  160. Bailey A., Luthert P., Dean A., et al. (1998) A clinicopathological study of autism. Brain 121 (Pt 5), 889–905.

    PubMed  Google Scholar 

  161. Guerin P., Lyon G., Barthelemy C., et al. (1996) Neuropathological study of a case of autistic syndrome with severe mental retardation. Dev Med Child Neurol 38, 203–211.

    PubMed  CAS  Google Scholar 

  162. Gupta S., Aggarwal S., Rashanravan B., Lee T. (1998) Th1- and Th2-like cytokines in CD4+ and CD8+ T cells in autism. J Neuroimmunol 85, 106–109.

    PubMed  CAS  Google Scholar 

  163. Singh V. K., Warren R., Averett R., Ghaziuddin M. (1997) Circulating autoantibodies to neuronal and glial filament proteins in autism. Pediatr Neurol 17, 88–90.

    PubMed  CAS  Google Scholar 

  164. Singh V. K., Lin S. X., Newell E., Nelson C. (2002) Abnormal measles-mumps-rubella antibodies and CNS autoimmunity in children with autism. J Biomed Sci 9, 359–364.

    PubMed  CAS  Google Scholar 

  165. Vojdani A., Campbell A. W., Anyanwu E., Kashanian A., Bock K., Vojdani E. (2002) Antibodies to neuron-specific antigens in children with autism: possible cross-reaction with encephalitogenic proteins from milk, Chlamydia pneumoniae and Streptococcus group A. J Neuroimmunol 129, 168–177.

    PubMed  CAS  Google Scholar 

  166. Jyonouchi H., Sun S., Le H. (2001) Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression. J Neuroimmunol 120, 170–179.

    PubMed  CAS  Google Scholar 

  167. Molloy C. A., Morrow A. L., Meinzen-Derr J., et al. (2006) Elevated cytokine levels in children with autism spectrum disorder. J Neuroimmunol 172, 198–205.

    PubMed  CAS  Google Scholar 

  168. Vargas D. L., Nascimbene C., Krishnan C., Zimmerman A. W., Pardo C. A. (2005) Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 57, 67–81.

    PubMed  CAS  Google Scholar 

  169. Gandhi R., Hayley S., Gibb J., Merali Z., Anisman H. (2007) Influence of poly I:C on sickness behaviors, plasma cytokines, corticosterone and central monoamine activity: moderation by social stressors. Brain Behav Immun 21, 477–489.

    Google Scholar 

  170. Hayley S., Poulter M. O., Merali Z., Anisman H. (2005) The pathogenesis of clinical depression: stressor- and cytokine-induced alterations of neuroplasticity. Neuroscience 135, 659–678.

    PubMed  CAS  Google Scholar 

  171. Cloez-Tayarani I., Changeux J. P. (2007) Nicotine and serotonin in immune regulation and inflammatory processes: a perspective. J Leukoc Biol 81, 599–606.

    PubMed  CAS  Google Scholar 

  172. Kushnir-Sukhov N. M., Gilfillan A. M., Coleman J. W., et al. (2006) 5-hydroxytryptamine induces mast cell adhesion and migration. J Immunol 177, 6422–6432.

    PubMed  CAS  Google Scholar 

  173. Katoh N., Soga F., Nara T., et al. (2006) Effect of serotonin on the differentiation of human monocytes into dendritic cells. Clin Exp Immunol 146, 354–361.

    PubMed  CAS  Google Scholar 

  174. Idzko M., Panther E., Stratz C., et al. (2004) The serotoninergic receptors of human dendritic cells: identification and coupling to cytokine release. J Immunol 172, 6011–6019.

    PubMed  CAS  Google Scholar 

  175. Tsao C. W., Lin Y. S., Chen C. C., Bai C. H., Wu S. R. (2006) Cytokines and serotonin transporter in patients with major depression. Prog Neuropsychopharmacol Biol Psychiatry 30, 899–905.

    PubMed  CAS  Google Scholar 

  176. Maes M., Ombelet W., De Jongh R., Kenis G., Bosmans E. (2001) The inflammatory response following delivery is amplified in women who previously suffered from major depression, suggesting that major depression is accompanied by a sensitization of the inflammatory response system. J Affect Disord 63, 85–92.

    PubMed  CAS  Google Scholar 

  177. Russo S., Kema I. P., Fokkema M. R., et al. (2003) Tryptophan as a link between psychopathology and somatic states. Psychosom Med 65, 665–671.

    PubMed  CAS  Google Scholar 

  178. Spalletta G., Bossu P., Ciaramella A., Bria P., Caltagirone C., Robinson R. G. (2006) The etiology of poststroke depression: a review of the literature and a new hypothesis involving inflammatory cytokines. Mol Psychiatry 11, 984–991.

    PubMed  CAS  Google Scholar 

  179. Capuron L., Miller A. H. (2004) Cytokines and psychopathology: lessons from interferon-alpha. Biol Psychiatry 56, 819–824.

    PubMed  CAS  Google Scholar 

  180. Schaefer M., Schwaiger M., Pich M., Lieb K., Heinz A. (2003) Neurotransmitter changes by interferon-alpha and therapeutic implications. Pharmacopsychiatry 36 Suppl 3, S203–S206.

    PubMed  CAS  Google Scholar 

  181. Sato T., Suzuki E., Yokoyama M., Semba J., Watanabe S., Miyaoka H. (2006) Chronic intraperitoneal injection of interferon-alpha reduces serotonin levels in various regions of rat brain, but does not change levels of serotonin transporter mRNA, nitrite or nitrate. Psychiatry Clin Neurosci 60, 499–506.

    PubMed  CAS  Google Scholar 

  182. Kamata M., Higuchi H., Yoshimoto M., Yoshida K., Shimizu T. (2000) Effect of single intracerebroventricular injection of alpha-interferon on monoamine concentrations in the rat brain. Eur Neuropsychopharmacol 10, 129–132.

    PubMed  CAS  Google Scholar 

  183. Foley K. F., Pantano C., Ciolino A., Mawe G. M. (2007) IFN-{gamma} and TNF-{alpha} decrease serotonin transporter function and expression in Caco2 cells. Am J Physiol Gastrointest Liver Physiol 292, G779–G784.

    PubMed  CAS  Google Scholar 

  184. Myint A. M., Kim Y. K. (2003) Cytokine-serotonin interaction through IDO: a neurodegeneration hypothesis of depression. Med Hypotheses 61, 519–525.

    PubMed  CAS  Google Scholar 

  185. Zhu C. B., Blakely R. D., Hewlett W. A. (2006) The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters. Neuropsychopharmacology 31, 2121–2131.

    PubMed  CAS  Google Scholar 

  186. Zhang J., Terreni L., De Simoni M. G., Dunn A. J. (2001) Peripheral interleukin-6 administration increases extracellular concentrations of serotonin and the evoked release of serotonin in the rat striatum. Neurochem Int 38, 303–308.

    PubMed  CAS  Google Scholar 

  187. Miyata M., Ito M., Sasajima T., Ohira H., Kasukawa R. (2001) Effect of a serotonin receptor antagonist on interleukin-6-induced pulmonary hypertension in rats. Chest 119, 554–561.

    PubMed  CAS  Google Scholar 

  188. Boylan C. B., Blue M. E., Hohmann C. F. (2007) Modeling early cortical serotonergic deficits in autism. Behav Brain Res 176, 94–108.

    PubMed  CAS  Google Scholar 

  189. Hohmann C. F., Walker E. M., Boylan C. B., Blue M. E. (2007) Neonatal serotonin depletion alters behavioral responses to spatial change and novelty. Brain Res 1139, 163–177.

    PubMed  CAS  Google Scholar 

  190. Hohmann C. F., Richardson C., Pitts E., Berger-Sweeney J. (2000) Neonatal 5,7-DHT lesions cause sex-specific changes in mouse cortical morphogenesis. Neural Plast 7, 213–232.

    PubMed  CAS  Google Scholar 

  191. Hardan A. Y., Muddasani S., Vemulapalli M., Keshavan M. S., Minshew N. J. (2006) An MRI study of increased cortical thickness in autism. Am J Psychiatry 163, 1290–1292.

    PubMed  Google Scholar 

  192. Courchesne E. (2002) Abnormal early brain development in autism. Mol Psychiatry 7 Suppl 2, S21–S23.

    PubMed  Google Scholar 

  193. Courchesne E., Carper R., Akshoomoff N. (2003) Evidence of brain overgrowth in the first year of life in autism. JAMA 290, 337–344.

    PubMed  Google Scholar 

  194. Courchesne E., Redcay E., Kennedy D. P. (2004) The autistic brain: birth through adulthood. Curr Opin Neurol 17, 489–496.

    PubMed  Google Scholar 

  195. Hazlett H. C., Poe M., Gerig G., et al. (2005) Magnetic resonance imaging and head circumference study of brain size in autism: birth through age 2 years. Arch Gen Psychiatry 62, 1366–1376.

    PubMed  Google Scholar 

  196. Aylward E., Minshew N., Field K., Sparks B., Singh N. (2002) Effects of age on brain volume and head circumference in autism. Neurology Jul 23;59(2), 175–183.

    CAS  Google Scholar 

  197. Redcay E., Courchesne E. (2005) When is the brain enlarged in autism? A meta-analysis of all brain size reports. Biol Psychiatry 58, 1–9.

    PubMed  Google Scholar 

  198. Sacco R., Militerni R., Frolli A., et al. (2007) Clinical, Morphological, and Biochemical Correlates of Head Circumference in Autism. Biol Psychiatry 62, 1038–1047.

    Google Scholar 

  199. Dziuk M. A., Gidley Larson J. C., Apostu A., Mahone E. M., Denckla M. B., Mostofsky S. H. (2007) Dyspraxia in autism: association with motor, social, and communicative deficits. Dev Med Child Neurol 49, 734–739.

    PubMed  CAS  Google Scholar 

  200. Shemer A. V., Azmitia E. C., Whitaker-Azmitia P. M. (1991) Dose-related effects of prenatal 5-methoxytryptamine (5-MT) on development of serotonin terminal density and behavior. Brain Res Dev Brain Res 59, 59–63.

    PubMed  CAS  Google Scholar 

  201. Kahne D., Tudorica A., Borella A., et al. (2002) Behavioral and magnetic resonance spectroscopic studies in the rat hyperserotonemic model of autism. Physiol Behav 75, 403–410.

    PubMed  CAS  Google Scholar 

  202. Chugani D. C., Sundram B. S., Behen M., Lee M. L., Moore G. J. (1999) Evidence of altered energy metabolism in autistic children. Prog Neuropsychopharmacol Biol Psychiatry 23, 635–641.

    PubMed  CAS  Google Scholar 

  203. Tsujino N., Nakatani Y., Seki Y., et al. (2007) Abnormality of circadian rhythm accompanied by an increase in frontal cortex serotonin in animal model of autism. Neurosci Res 57, 289–295.

    PubMed  CAS  Google Scholar 

  204. Schneider T., Przewlocki R. (2005) Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology 30, 80–89.

    PubMed  CAS  Google Scholar 

  205. Markram K., Rinaldi T., Mendola D. L., Sandi C., Markram H. (2007) Abnormal fear conditioning and amygdala processing in an animal model of autism. Neuropsychopharmacology 62, 901–912.

    Google Scholar 

  206. Rinaldi T., Kulangara K., Antoniello K., Markram H. (2007) Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid. Proc Natl Acad Sci U S A 104, 13501–13506.

    PubMed  CAS  Google Scholar 

  207. Rinaldi T., Silberberg G., Markram H. (2007) Hyperconnectivity of local neocortical microcircuitry induced by prenatal exposure to valproic acid. Cereb Cortex 18, 763–770.

    Google Scholar 

  208. Narita N., Kato M., Tazoe M., Miyazaki K., Narita M., Okado N. (2002) Increased monoamine concentration in the brain and blood of fetal thalidomide- and valproic acid-exposed rat: putative animal models for autism. Pediatr Res 52, 576–579.

    PubMed  CAS  Google Scholar 

  209. Miyazaki K., Narita N., Narita M. (2005) Maternal administration of thalidomide or valproic acid causes abnormal serotonergic neurons in the offspring: implication for pathogenesis of autism. Int J Dev Neurosci 23, 287–297.

    PubMed  CAS  Google Scholar 

  210. Rodier P. M., Ingram J. L., Tisdale B., Croog V. J. (1997) Linking etiologies in humans and animal models: studies of autism. Reprod Toxicol 11, 417–422.

    PubMed  CAS  Google Scholar 

  211. Arndt T. L., Stodgell C. J., Rodier P. M. (2005) The teratology of autism. Int J Dev Neurosci 23, 189–199.

    PubMed  CAS  Google Scholar 

  212. Rodier P. M. (2002) Converging evidence for brain stem injury in autism. Dev Psychopathol 14, 537–557.

    PubMed  Google Scholar 

  213. Ingram J. L., Stodgell C. J., Hyman S. L., Figlewicz D. A., Weitkamp L. R., Rodier P. M. (2000) Discovery of allelic variants of HOXA1 and HOXB1: genetic susceptibility to autism spectrum disorders. Teratology 62, 393–405.

    PubMed  CAS  Google Scholar 

  214. Trottier G., Srivastava L., Walker C. D. (1999) Etiology of infantile autism: a review of recent advances in genetic and neurobiological research. J Psychiatry Neurosci 24, 103–115.

    PubMed  CAS  Google Scholar 

  215. Ijichi S., Ijichi N. (2002) Minor form of trigonocephaly is an autistic skull shape? A suggestion based on homeobox gene variants and MECP2 mutations. Med Hypotheses 58, 337–339.

    PubMed  CAS  Google Scholar 

  216. Rossel M., Capecchi M. R. (1999) Mice mutant for both Hoxa1 and Hoxb1 show extensive remodeling of the hindbrain and defects in craniofacial development. Development 126, 5027–5040.

    PubMed  CAS  Google Scholar 

  217. Shuey D. L., Yavarone M., Sadler T. W., Lauder J. M. (1990) Serotonin and morphogenesis in the cultured mouse embryo. Adv Exp Med Biol 265, 205–215.

    PubMed  CAS  Google Scholar 

  218. Gharani N., Benayed R., Mancuso V., Brzustowicz L. M., Millonig J. H. (2004) Association of the homeobox transcription factor, ENGRAILED 2, 3, with autism spectrum disorder. Mol Psychiatry 9, 474–484.

    PubMed  CAS  Google Scholar 

  219. Benayed R., Gharani N., Rossman I., et al. (2005) Support for the homeobox transcription factor gene ENGRAILED 2 as an autism spectrum disorder susceptibility locus. Am J Hum Genet 77, 851–868.

    PubMed  CAS  Google Scholar 

  220. Zhong H., Serajee F. J., Nabi R., Huq A. H. (2003) No association between the EN2 gene and autistic disorder. J Med Genet 40, e4.

    PubMed  CAS  Google Scholar 

  221. Cheh M. A., Millonig J. H., Roselli L. M., et al. (2006) En2 knockout mice display neurobehavioral and neurochemical alterations relevant to autism spectrum disorder. Brain Res 1116, 166–176.

    PubMed  CAS  Google Scholar 

  222. Kuemerle B., Gulden F., Cherosky N., Williams E., Herrup K. (2007) The mouse Engrailed genes: a window into autism. Behav Brain Res 176, 121–132.

    PubMed  CAS  Google Scholar 

  223. Aldridge J. E., Levin E. D., Seidler F. J., Slotkin T. A. (2005) Developmental exposure of rats to chlorpyrifos leads to behavioral alterations in adulthood, involving serotonergic mechanisms and resembling animal models of depression. Environ Health Perspect 113, 527–531.

    PubMed  Google Scholar 

  224. Aldridge J. E., Meyer A., Seidler F. J., Slotkin T. A. (2005) Alterations in central nervous system serotonergic and dopaminergic synaptic activity in adulthood after prenatal or neonatal chlorpyrifos exposure. Environ Health Perspect 113, 1027–1031.

    PubMed  CAS  Google Scholar 

  225. Beyrouty P., Stamler C. J., Liu J. N., Loua K. M., Kubow S., Chan H. M. (2006) Effects of prenatal methylmercury exposure on brain monoamine oxidase activity and neurobehaviour of rats. Neurotoxicol Teratol 28, 251–259.

    PubMed  CAS  Google Scholar 

  226. Khan I. A., Thomas P. (2004) Aroclor 1254 inhibits tryptophan hydroxylase activity in rat brain. Arch Toxicol 78, 316–320.

    PubMed  CAS  Google Scholar 

  227. Mariussen E., Fonnum F. (2001) The effect of polychlorinated biphenyls on the high affinity uptake of the neurotransmitters, dopamine, serotonin, glutamate and GABA, into rat brain synaptosomes. Toxicology 159, 11–21.

    PubMed  CAS  Google Scholar 

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Blue, M.E., Johnston, M.V., Moloney, C.B., Hohmann, C.F. (2008). Serotonin Dysfunction in Autism. In: Autism. Current Clinical Neurology. Humana Press. https://doi.org/10.1007/978-1-60327-489-0_5

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