Skip to main content
SpringerLink
Log in

Evidence for Environmental Susceptibility in Autism

What We Need to Know About Gene × Environment Interactions

  • Chapter
Autism

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

Abstract

Research into the pathophysiology and genetics of autism may inform the identification of environmental susceptibility factors that promote adverse outcomes in brain development. Conversely, understanding how low-level chemical exposure influences molecular, cellular, and behavioral outcomes relevant to the development of autism will enlighten geneticists, neuroscientists, and immunologists about autism’s complex etiologies and possibly yield novel intervention strategies. The inherent imbalances in neuronal connectivity in children at risk for autism are likely to provide the biological substrate for enhanced susceptibility to environmental triggers that are known to target signaling systems that establish the basic patterns of connectivity, from early neuronal migration and axonal pathfinding to postnatal refining of neuronal connections. Three examples of gene × environment interactions that likely contribute to autism risk are illustrated: pesticides that interfere with (1) acetylcholine (ACh) and (2) γ-aminobutyric acid (GABA) neurotransmission; and (3) the persistent organic pollutants that directly alter Ca2+ signaling pathways and Ca2+-dependent effectors. One fundamental way in which heritable genetic vulnerabilities can amplify the adverse effects triggered by environmental exposures is if both factors (genes and environment) converge to dysregulate the same neurotransmitter and/or signaling systems at critical times during development.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders DMS-IV-TR (Text Revision) Washington D.C., American Psychiatric Association, 2000.

    Google Scholar 

  2. Fombonne E. The prevalence of autism. J Am Med Assoc 2003;289:87–89.

    Google Scholar 

  3. Rice C. Prevalence of Autism Spectrum Disorders. MMWR, Centers for Disease Control 2000;56(SS01):1–11.

    Google Scholar 

  4. Wassink TH, Piven J. The molecular genetics of autism. Curr Psychiatry Rep 2000;2:170–175.

    PubMed  CAS  Google Scholar 

  5. Veenstra-Vanderweele J, Christian SL, Cook EH Jr. Autism as a paradigmatic complex genetic disorder. Annu Rev Genomics Hum Genet 2004;5:379–405.

    PubMed  CAS  Google Scholar 

  6. Pickles A, Bolton P, Macdonald H, Bailey A, Le Couteur A, Sim CH, Rutter, M. Latent-class analysis of recurrence risk for complex phenotypes with selection and measurement error: a twin and family history study of autism. Am J Hum Genet 1995;57:717–726.

    PubMed  CAS  Google Scholar 

  7. Folstein SE, Rosen-Sheidley B. Genetics of autism: complex aetiology for a heterogeneous disorder. Nat Rev Genet 2001;2:943–955.

    PubMed  CAS  Google Scholar 

  8. Risch N, Spiker D, Lotspeich L, Nouri N, Hinds D, Hallmayer J, Kalaydjieva L, McCague P, Dimiceli S, Pitts T, Nguyen L, Yang J, Harper C, Thorpe D, Vermeer S, Young H, Hebert J, Lin A, Ferguson J, Chiotti C, Wiese-Slater S, Rogers T, Salmon B, Nicholas P, Petersen PB, Pingree C, McMahon W, Wong DL, Cavalli-Sforza LL, Kraemer HC, Myers RM. A genomic screen of autism: evidence for a multilocus etiology. Am J Hum Genet 1999;65:493–507.

    PubMed  CAS  Google Scholar 

  9. Pritchard JK. Are rare variants responsible for susceptibility to complex diseases? Am J Hum Genet 2001;69:124–137.

    PubMed  CAS  Google Scholar 

  10. Trikalinos TA, Karvouni A, Zintzaras E, Ylisaukko-Oja T, Peltonen L, Jarvela I, Ioannidis JP. A heterogeneity-based genome search meta-analysis for autism-spectrum disorders. Mol Psychiatry 2005;11:29–36.

    Google Scholar 

  11. Maestrini E, Paul A, Monaco AP, Bailey A. Identifying autism susceptibility genes. Neuron 2000;28:19–24.

    PubMed  CAS  Google Scholar 

  12. Muhle R, Trentacoste SV, Rapin I. The genetics of autism. Pediatrics 2004;113:472–486.

    Google Scholar 

  13. Mills JL, Hediger ML, Molloy CA, Chrousos GP, Manning-Courtney P, Yu KF, Brasington M, England LJ. Elevated levels of growth-related hormones in autism and autism spectrum disorder. Clin Endocrinol (Oxf) 2007;67:230–237.

    CAS  Google Scholar 

  14. Kaminsky Z, Wang SC, Petronis A. Complex disease, gender and epigenetics. Ann Med 2006;38:530–44.

    PubMed  CAS  Google Scholar 

  15. Arndt TL, Stodgell CJ, Rodier PM. The teratology of autism. Int J Dev Neurosci 2005;23:189–199.

    PubMed  CAS  Google Scholar 

  16. Miller MT, Stromland K, Ventura L, Johansson M, Bandim JM, Gillberg C. Autism associated with conditions characterized by developmental errors in early embryogenesis: a mini review. Int J Dev Neurosci 2005;23:201–219.

    PubMed  Google Scholar 

  17. Muller RA. The study of autism as a distributed disorder. Ment Retard Dev Disabil Res Rev 2007;13:85–95.

    PubMed  Google Scholar 

  18. Rubenstein JL, Merzenich MM. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav 2003;2:255–267.

    PubMed  CAS  Google Scholar 

  19. Belmonte MK, Bourgeron T. Fragile X syndrome and autism at the intersection of genetic and neural networks. Nat Neurosci 2006;9:1221–1225.

    PubMed  CAS  Google Scholar 

  20. Geschwind DH, Levitt P. Autism spectrum disorders: developmental disconnection syndromes. Curr Opin Neurobiol 2007;17:103–111.

    PubMed  CAS  Google Scholar 

  21. DiCicco-Bloom E, Lord C, Zwaigenbaum L, Courchesne E, Dager SR, Schmitz C, Schultz RT, Crawley J, Young LJ. The developmental neurobiology of autism spectrum disorder. J Neurosci 2006; 26:6897–6906.

    PubMed  CAS  Google Scholar 

  22. Donaldson D, Kiely T, Grube A. Pesticides Industry Sales and Usage 1998 and 1999 Market Estimates. Washington, DC:U.S. Environmental Protection Agency, Office of Prevention, Pesticides, and Toxic Substances, Office of Pesticide Programs, 2002.

    Google Scholar 

  23. Pope CN. Organophosphorus pesticides: do they all have the same mechanism of toxicity? J Toxicol Environ Health B Crit Rev 1999;2:161–181.

    PubMed  CAS  Google Scholar 

  24. Schuh RA, Lein PJ, Beckles RA, Jett DA. Noncholinesterase mechanisms of chlorpyrifos neurotoxicity: altered phosphorylation of Ca2+/cAMP response element binding protein in cultured neurons. Toxicol Appl Pharmacol 2002;182:176–185.

    PubMed  CAS  Google Scholar 

  25. Jameson RR, Seidler FJ, Slotkin TA. Nonenzymatic functions of acetylcholinesterase splice variants in the developmental neurotoxicity of organophosphates: chlorpyrifos, chlorpyrifos oxon, and diazinon. Environ Health Perspect 2007;115:65–70.

    PubMed  CAS  Google Scholar 

  26. Ricceri L, Venerosi A, Capone F, Cometa MF, Lorenzini P, Fortuna S, Calamandrei G. Developmental neurotoxicity of organophosphorous pesticides: fetal and neonatal exposure to chlorpyrifos alters sex-specific behaviors at adulthood in mice. Toxicol Sci 2006;93:105–113.

    PubMed  CAS  Google Scholar 

  27. Slotkin TA, Seidler FJ, Fumagalli F. Exposure to organophosphates reduces the expression of neurotrophic factors in neonatal rat brain regions: similarities and differences in the effects of chlorpyrifos and diazinon on the fibroblast growth factor superfamily. Environ Health Perspect 2007;115:909–916.

    PubMed  CAS  Google Scholar 

  28. Peltier J, O'neill A, Schaffer DV. PI3K/Akt and CREB regulate adult neural hippocampal progenitor proliferation and differentiation. Dev Neurobiol 2007;67:1348–1361.

    PubMed  CAS  Google Scholar 

  29. Redmond L, Ghosh A. Regulation of dendritic development by calcium signaling. Cell Calcium 2005;37:411–416.

    PubMed  CAS  Google Scholar 

  30. Stachowiak MK, Fang X, Myers JM, Dunham SM, Berezney R, Maher PA, Stachowiak EK. Integrative nuclear FGFR1 signaling (INFS) as a part of a universal “feed-forward-and-gate” signaling module that controls cell growth and differentiation. J Cell Biochem 2003;90:662–691.

    PubMed  CAS  Google Scholar 

  31. Tomizawa M, Casida JE. Neonicotinoid insecticide toxicology: mechanisms of selective action. Annu Rev Pharmacol Toxicol 2005;45:247–268.

    PubMed  CAS  Google Scholar 

  32. Gotti C, Zoli M, Clementi F. Brain nicotinic acetylcholine receptors: native subtypes and their relevance. Trends Pharmacol Sci 2006;27:482–491.

    PubMed  CAS  Google Scholar 

  33. Martin-Ruiz CM, Lee M, Perry RH, Baumann M, Court JA, Perry EK. Molecular analysis of nicotinic receptor expression in autism. Brain Res Mol Brain Res 2004;123:81–90.

    PubMed  CAS  Google Scholar 

  34. Lee M, Martin-Ruiz C, Graham A, Court J, Jaros E, Perry R, Iversen P, Bauman M, Perry E. Nicotinic receptor abnormalities in the cerebellar cortex in autism. Brain 2002;125:1483–1495.

    PubMed  CAS  Google Scholar 

  35. Perry EK, Lee ML, Martin-Ruiz CM, et al Cholinergic activity in autism: abnormalities in the cerebral cortex and basal forebrain. Am J Psychiatry 2001;158:1058–1066.

    PubMed  CAS  Google Scholar 

  36. D'Amelio M, Ricci I, Sacco R, Liu X, D'Agruma L, Muscarella LA, Guarnieri V, Militerni R, Bravaccio C, Elia M, Schneider C, Melmed R, Trillo S, Pascucci T, Puglisi-Allegra S, Reichelt KL, Macciardi F, Holden JJ, Persico AM. Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions. Mol Psychiatry 2005;10:1006–1016.

    PubMed  Google Scholar 

  37. Pasca SP, Nemes B, Vlase L, Gagyi CE, Dronca E, Miu AC, Dronca M. High levels of homocysteine and low serum paraoxonase 1 arylesterase activity in children with autism. Life Sci 2006;78:2244–2248.

    PubMed  CAS  Google Scholar 

  38. Hertz-Picciotto I, Croen LA, Hansen R, Jones CR, van de Water J, Pessah IN. The CHARGE study: an epidemiologic investigation of genetic and environmental factors contributing to autism. Environ Health Perspect 2006;114:1119–1125.

    PubMed  Google Scholar 

  39. Eskenazi B, Marks AR, Bradman A, Harley K, Barr DB, Johnson C, Morga N, Jewell NP. Organophosphate pesticide exposure and neurodevelopment in young Mexican-American children. Environ Health Perspect 2007;115:792–798.

    PubMed  CAS  Google Scholar 

  40. Michels G, Moss SJ. GABAA receptors: properties and trafficking. Crit Rev Biochem Mol Biol 2007;42:3–14.

    PubMed  CAS  Google Scholar 

  41. Lu J, Karadsheh M, Delpire E. Developmental regulation of the neuronal-specific isoform of K-Cl cotransporter KCC2 in postnatal rat brains. J Neurobiol 1999;39:558–568.

    PubMed  CAS  Google Scholar 

  42. Cole LM, Casida JE. Polychlorocycloalkane insecticide-induced convulsions in mice in relation to disruption of the GABA-regulated chloride ionophore. Life Sci 1986;39:1855–1862.

    PubMed  CAS  Google Scholar 

  43. Lawrence LJ, Casida JE. Interactions of lindane, toxaphene and cyclodienes with brain-specific t-butylbicyclophosphorothionate receptor. Life Sci 1984;35:171–178.

    PubMed  CAS  Google Scholar 

  44. Slotkin TA, MacKillop EA, Ryde IT, Tate CA, Seidler FJ. Screening for developmental neurotoxicity using PC12 cells: comparisons of organophosphates with a carbamate, an organochlorine, and divalent nickel. Environ Health Perspect 2007;115:93–101.

    PubMed  CAS  Google Scholar 

  45. Bloomquist JR. Chloride channels as tools for developing selective insecticides. Arch Insect Biochem Physiol 2003;54:145–156.

    PubMed  CAS  Google Scholar 

  46. Chen L, Durkin KA, Casida JE. Structural model for gamma-aminobutyric acid receptor noncompetitive antagonist binding: widely diverse structures fit the same site. Proc Natl Acad Sci U S A 2006;103:5185–5190.

    PubMed  CAS  Google Scholar 

  47. Sammelson RE, Caboni P, Durkin KA, Casida JE. GABA receptor antagonists and insecticides: common structural features of 4-alkyl-1-phenylpyrazoles and 4-alkyl-1-phenyltrioxabicyclooctanes. Bioorg Med Chem 2004;12:3345–3355.

    PubMed  CAS  Google Scholar 

  48. Samaco RC, Hogart A, LaSalle JM. Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3. Hum Mol Genet 2005;14:483–492.

    PubMed  CAS  Google Scholar 

  49. LaSalle JM, Hogart A, Thatcher KN. Rett syndrome: a Rosetta stone for understanding the molecular pathogenesis of autism. Int Rev Neurobiol 2005;71:131–165.

    PubMed  CAS  Google Scholar 

  50. Vincent JB, Horike SI, Choufani S, Paterson AD, Roberts W, Szatmari P, Weksberg R, Fernandez B, Scherer SW. An inversion inv(4)(p12–p15.3) in autistic siblings implicates the 4p GABA receptor gene cluster. J Med Genet 2006;43:429–434.

    PubMed  CAS  Google Scholar 

  51. Ashley-Koch AE, Mei H, Jaworski J, Ma DQ, Ritchie MD, Menold MM, Delong GR, Abramson RK, Wright HH, Hussman JP, Cuccaro ML, Gilbert JR, Martin ER, Pericak-Vance MA. An analysis paradigm for investigating multi-locus effects in complex disease: examination of three GABA receptor subunit genes on 15q11–q13 as risk factors for autistic disorder. Ann Hum Genet 2006;70:281–292.

    PubMed  CAS  Google Scholar 

  52. Ma DQ, Whitehead PL, Menold MM, Martin ER, Ashley-Koch AE, Mei H, Ritchie MD, Delong GR, Abramson RK, Wright HH, Cuccaro ML, Hussman JP, Gilbert JR, Pericak-Vance MA. Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism. Am J Hum Genet 2005;77:377–388.

    PubMed  CAS  Google Scholar 

  53. Roberts EM, English PB, Grether JK, Windham GC, Somberg L, Wolff C. Maternal residence near agricultural pesticide applications and autism spectrum disorders among children in the California Central Valley. Env Health Perspect 2007;115:1482–1489.

    Google Scholar 

  54. Berridge MJ. Calcium microdomains: organization and function. Cell Calcium 2006;40:405–412.

    PubMed  CAS  Google Scholar 

  55. Lyons HR, Land MB, Gibbs TT, Farb DH. Distinct signal transduction pathways for GABA-induced GABA(A) receptor down-regulation and uncoupling in neuronal culture: a role for voltage-gated calcium channels. J Neurochem 2001;78:1114–1126.

    Google Scholar 

  56. Dale YR, Eltom SE. Calpain mediates the dioxin-induced activation and down-regulation of the aryl hydrocarbon receptor. Mol Pharmacol 2006;70:1481–1487.

    PubMed  CAS  Google Scholar 

  57. Pessah IN, Hansen LG, Albertson TE, Garner CE, Ta TA, Do Z, Kim KH, Wong PW. Structure-activity relationship for noncoplanar polychlorinated biphenyl congeners toward the ryanodine receptor-Ca2+ channel complex type 1 (RyR1). Chem Res Toxicol 2006;19:92–101.

    PubMed  CAS  Google Scholar 

  58. Wong PW, Brackney WR, Pessah IN. Ortho-substituted polychlorinated biphenyls alter microsomal calcium transport by direct interaction with ryanodine receptors of mammalian brain. J Biol Chem 1997;272:15145–1553.

    PubMed  CAS  Google Scholar 

  59. Gafni J, Wong PW, Pessah IN. Non-coplanar 2,2′,3,5′,6-pentachlorobiphenyl (PCB 95) amplifies ionotropic glutamate receptor signaling in embryonic cerebellar granule neurons by a mechanism involving ryanodine receptors. Toxicol Sci 2004;77:72–82.

    PubMed  CAS  Google Scholar 

  60. Wong PW, Garcia EF, Pessah IN. Ortho-substituted PCB95 alters intracellular calcium signaling and causes cellular acidification in PC12 cells by an immunophilin-dependent mechanism. J Neurochem 2001;76:450–463.

    PubMed  CAS  Google Scholar 

  61. Howard AS, Fitzpatrick R, Pessah I, Kostyniak P, Lein PJ. Polychlorinated biphenyls induce caspase-dependent cell death in cultured embryonic rat hippocampal but not cortical neurons via activation of the ryanodine receptor. Toxicol Appl Pharmacol 2003;190:72–86.

    PubMed  CAS  Google Scholar 

  62. Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, Napolitano C, Schwartz PJ, Joseph RM, Condouris K, Tager-Flusberg H, Priori SG, Sanguinetti MC, Keating MT. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 2004;119:19–31.

    PubMed  CAS  Google Scholar 

  63. Komuro H, Rakic P. Orchestration of neuronal migration by activity of ion channels, neurotransmitter receptors, and intracellular Ca2+ fluctuations. J Neurobiol 1998;37:110–130.

    PubMed  CAS  Google Scholar 

  64. Aamodt SM, Constantine-Paton M. The role of neural activity in synaptic development and its implications for adult brain function. Adv Neurol 1999;79:133–144.

    PubMed  CAS  Google Scholar 

  65. Cline HT. Dendritic arbor development and synaptogenesis. Curr Opin Neurobiol 2001;11:118–126.

    PubMed  CAS  Google Scholar 

  66. Levitt P. Structural and functional maturation of the developing primate brain. J Pediatr 2003;143:S35–45.

    PubMed  CAS  Google Scholar 

  67. Moody WJ, Bosma MM. Ion channel development, spontaneous activity, and activity-dependent development in nerve and muscle cells. Physiol Rev 2005;85:883–941.

    PubMed  CAS  Google Scholar 

  68. Krey JF, Dolmetsch RE. Molecular mechanisms of autism: a possible role for Ca2+ signaling. Curr Opin Neurobiol 2007;17:112–119.

    PubMed  CAS  Google Scholar 

  69. Kenet T, Froemke RC, Schreiner CE, Pessah IN, Merzenich MM. Perinatal exposure to a noncoplanar polychlorinated biphenyl alters tonotopy, receptive fields, and plasticity in rat primary auditory cortex. Proc Natl Acad Sci U S A 2007;104:7646–7651.

    PubMed  CAS  Google Scholar 

  70. Lein PJ, Yang D, Bachstetter AD, Tilson HA, Harry GJ, Mervis RF, Kodavanti PR. Ontogenetic alterations in molecular and structural correlates of dendritic growth after developmental exposure to polychlorinated biphenyls. Environ Health Perspect 2007;115:556–563.

    PubMed  CAS  Google Scholar 

  71. Engert F, Bonhoeffer T. Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature 1999;399:66–70.

    PubMed  CAS  Google Scholar 

  72. Purves D. Body and Brain: A Trophic Theory of Neural Connections. Cambridge, MA: Harvard University Press; 1988.

    Google Scholar 

  73. Miller JP, Jacobs GA. Relationships between neuronal structure and function. J Exp Biol 1984;112:129–145.

    PubMed  CAS  Google Scholar 

  74. Schuman EM. Synapse specificity and long-term information storage. Neuron 1997;18:339–342.

    PubMed  CAS  Google Scholar 

  75. Sejnowski TJ. The year of the dendrite. Science 1997;275:178–179.

    PubMed  CAS  Google Scholar 

  76. Scott EK, Luo L. How do dendrites take their shape? Nat Neurosci 2001;4:359–365.

    PubMed  CAS  Google Scholar 

  77. Grutzendler J, Gan WB. Two-photon imaging of synaptic plasticity and pathology in the living mouse brain. NeuroRx 2006;3:489–496.

    PubMed  Google Scholar 

  78. Harms KJ, Dunaevsky A. Dendritic spine plasticity: looking beyond development. Brain Res 2007;1184:65–71 [Epub 2006 Apr 5]

    PubMed  CAS  Google Scholar 

  79. Le Be JV, Markram H. Spontaneous and evoked synaptic rewiring in the neonatal neocortex. Proc Natl Acad Sci U S A 2006;103:13214–13219.

    PubMed  Google Scholar 

  80. Sorra KE, Harris KM. Overview on the structure, composition, function, development, and plasticity of hippocampal dendritic spines. Hippocampus 2000;10:501–511.

    PubMed  CAS  Google Scholar 

  81. Hering H, Sheng M. Dendritic spines: structure, dynamics and regulation. Nat Rev Neurosci 2001;2:880–888.

    PubMed  CAS  Google Scholar 

  82. Pittenger C, Kandel ER. In search of general mechanisms for long-lasting plasticity: Aplysia and the hippocampus. Philos Trans R Soc Lond B Biol Sci 2003;358:757–763.

    PubMed  Google Scholar 

  83. Leuner B, Shors TJ. New spines, new memories. Mol Neurobiol 2004;29:117–130.

    PubMed  CAS  Google Scholar 

  84. Segal M, Korkotian E, Murphy DD. Dendritic spine formation and pruning: common cellular mechanisms? Trends Neurosci 2000;23:53–57.

    PubMed  CAS  Google Scholar 

  85. Lohmann C, Wong RO. Regulation of dendritic growth and plasticity by local and global calcium dynamics. Cell Calcium 2005;37:403–409.

    PubMed  CAS  Google Scholar 

  86. Korkotian E, Segal M. Release of calcium from stores alters the morphology of dendritic spines in cultured hippocampal neurons. Proc Natl Acad Sci USA 1999;96:12068–12072.

    PubMed  CAS  Google Scholar 

  87. Redmond L, Kashani AH, Ghosh A. Calcium regulation of dendritic growth via CaM kinase IV and CREB-mediated transcription. Neuron 2002;34:999–1010.

    PubMed  CAS  Google Scholar 

  88. Wilson MT, Kisaalita WS, Keith CH. Glutamate-induced changes in the pattern of hippocampal dendrite outgrowth: a role for calcium-dependent pathways and the microtubule cytoskeleton. J Neurobiol 2000;43:159–172.

    PubMed  CAS  Google Scholar 

  89. Gomez-Ospina N, Tsuruta F, Barreto-Chang O, Hu L, Dolmetsch R. The C terminus of the L-type voltage-gated calcium channel Ca(V)1.2 encodes a transcription factor. Cell 2006;127:591–606.

    PubMed  CAS  Google Scholar 

  90. Courchesne E, Redcay E, Morgan JT, Kennedy DP. Autism at the beginning: microstructural and growth abnormalities underlying the cognitive and behavioral phenotype of autism. Dev Psychopathol 2005;17:577–597.

    PubMed  Google Scholar 

  91. Wayman GA, Impey S, Marks D, Saneyoshi T, Grant WF, Derkach V, Soderling TR. Activity-dependent dendritic arborization mediated by CaM-kinase I activation and enhanced CREB-dependent transcription of Wnt-2. Neuron 2006;50:897–909.

    PubMed  CAS  Google Scholar 

  92. Ou LC, Gean PW. Transcriptional regulation of brain-derived neurotrophic factor in the amygdala during consolidation of fear memory. Mol Pharmacol 2007;72:350–358.

    PubMed  CAS  Google Scholar 

  93. Chen WG, Chang Q, Lin Y, Meissner A, West AE, Griffith EC, Jaenisch R, Greenberg ME. Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 2003;302:885–889.

    PubMed  CAS  Google Scholar 

  94. Zhou Z, Hong EJ, Cohen S, Zhao WN, Ho HY, Schmidt L, Chen WG, Lin Y, Savner E, Griffith EC, Hu L, Steen JA, Weitz CJ, Greenberg ME. Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron 2006;52:255–269.

    PubMed  CAS  Google Scholar 

  95. Takei N, Inamura N, Kawamura M, Namba H, Hara K, Yonezawa K, Nawa H. Brain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites. J Neurosci 2004;24:9760–9769.

    PubMed  CAS  Google Scholar 

  96. Jaworski J, Spangler S, Seeburg DP, Hoogenraad CC, Sheng M. Control of dendritic arborization by the phosphoinositide-3′-kinase-Akt-mammalian target of rapamycin pathway. J Neurosci 2005;25:11300–11312.

    PubMed  CAS  Google Scholar 

  97. Kumar V, Zhang MX, Swank MW, Kunz J, Wu GY. Regulation of dendritic morphogenesis by Ras-PI3K-Akt-mTOR and Ras-MAPK signaling pathways. J Neurosci 2005;25:11288–11299.

    PubMed  CAS  Google Scholar 

  98. Gong R, Park CS, Abbassi NR, Tang SJ. Roles of glutamate receptors and the mammalian target of rapamycin (mTOR) signaling pathway in activity-dependent dendritic protein synthesis in hippocampal neurons. J Biol Chem 2006;281:18802–18815.

    PubMed  CAS  Google Scholar 

  99. Kishi N, Macklis JD. MECP2 is progressively expressed in post-migratory neurons and is involved in neuronal maturation rather than cell fate decisions. Mol Cell Neurosci 2004;27:306–321.

    PubMed  CAS  Google Scholar 

  100. Fukuda T, Itoh M, Ichikawa T, Washiyama K, Goto Y. Delayed maturation of neuronal architecture and synaptogenesis in cerebral cortex of Mecp2-deficient mice. J Neuropathol Exp Neurol 2005;64:537–544.

    PubMed  CAS  Google Scholar 

  101. Kwon CH, Luikart BW, Powell CM, Zhou J, Matheny SA, Zhang W, Li Y, Baker SJ, Parada LF. Pten regulates neuronal arborization and social interaction in mice. Neuron 2006;50:377–388.

    PubMed  CAS  Google Scholar 

  102. Wassink TH, Piven J, Vieland VJ, Huang J, Swiderski RE, Pietila J, Braun T, Beck G, Folstein SE, Haines JL, Sheffield VC. Evidence supporting WNT2 as an autism susceptibility gene. Am J Med Genet 2001;105:406–413.

    Google Scholar 

  103. Moretti P, Zoghbi HY. MeCP2 dysfunction in Rett syndrome and related disorders. Curr Opin Genet Dev 2006;16:276–281.

    PubMed  Google Scholar 

  104. Goffin A, Hoefsloot LH, Bosgoed E, Swillen A, Fryns JP. PTEN mutation in a family with Cowden syndrome and autism. Am J Med Genet 2001;105:521–524.

    PubMed  CAS  Google Scholar 

  105. Butler MG, Dasouki MJ, Zhou XP, Talebizadeh Z, Brown M, Takahashi TN, Miles JH, Wang CH, Stratton R, Pilarski R, Eng C. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J Med Genet 2005;42:318–321.

    PubMed  CAS  Google Scholar 

  106. Schantz SL, Seo BW, Wong PW, Pessah IN. Long-term effects of developmental exposure to 2,2′,3,5′,6-pentachlorobiphenyl (PCB 95) on locomotor activity, spatial learning and memory and brain ryanodine binding. Neurotoxicology 1997;18:457–467.

    PubMed  CAS  Google Scholar 

  107. Wong PW, Joy RM, Albertson TE, Schantz SL, Pessah IN. Ortho-substituted 2,2′,3,5′,6-pentachlorobiphenyl (PCB 95) alters rat hippocampal ryanodine receptors and neuroplasticity in vitro: evidence for altered hippocampal function. Neurotoxicology 1997;18:443–456.

    PubMed  CAS  Google Scholar 

  108. Wong PW, Pessah IN. Ortho-substituted polychlorinated biphenyls alter calcium regulation by a ryanodine receptor-mediated mechanism: structural specificity toward skeletal – and cardiac-type microsomal calcium release channels. Mol Pharmacol 1996;49:740–751.

    PubMed  CAS  Google Scholar 

  109. Pessah IN, Kim KH, Feng W. Redox sensing properties of the ryanodine receptor complex. Front Biosci 2002;7:a72–a79.

    PubMed  CAS  Google Scholar 

  110. Kennedy MB. Signal-processing machines at the postsynaptic density. Science 2000;290:750–754.

    PubMed  CAS  Google Scholar 

  111. Matus A. Actin-based plasticity in dendritic spines. Science 2000;290:754–758.

    PubMed  CAS  Google Scholar 

  112. Segal M. New building blocks for the dendritic spine. Neuron 2001;31:169–171.

    PubMed  CAS  Google Scholar 

  113. Deisseroth K, Heist EK, Tsien RW. Translocation of calmodulin to the nucleus supports CREB phosphorylation in hippocampal neurons. Nature 1998;392:198–202.

    PubMed  CAS  Google Scholar 

  114. Wang Y, Wu J, Rowan MJ, Anwyl R. Ryanodine produces a low frequency stimulation-induced NMDA receptor-independent long-term potentiation in the rat dentate gyrus in vitro. J Physiol 1996;495:755–767.

    PubMed  CAS  Google Scholar 

  115. Wang Y, Rowan MJ, Anwyl R. Induction of LTD in the dentate gyrus in vitro is NMDA receptor independent, but dependent on Ca2+ influx via low-voltage-activated Ca2+ channels and release of Ca2+ from intracellular stores. J Neurophysiol 1997;77:812–825.

    PubMed  CAS  Google Scholar 

  116. Li ST, Kato K, Mikoshiba K. Effect of calcineurin inhibitors on long-term depression in CA1 rat hippocampal neurons. 28th Annu Meet Soc Neurosci Abs 1998;24:1815.

    Google Scholar 

  117. Wong PW, Pessah IN. Noncoplanar PCB 95 alters microsomal calcium transport by an immunophilin FKBP12-dependent mechanism. Mol Pharmacol 1997;51(5):693–702.

    PubMed  CAS  Google Scholar 

  118. Alkon DL, Nelson TJ, Zhao W, Cavallaro S. Time domains of neuronal Ca2+ signaling and associative memory: steps through a calexcitin, ryanodine receptor, K+ channel cascade. Trends Neurosci 1998;21:529–537.

    PubMed  CAS  Google Scholar 

  119. Cavallaro S, Meiri N, Yi CL, Musco S, Ma W, Goldberg J, Alkon DL. Late memory-related genes in the hippocampus revealed by RNA fingerprinting. Proc Natl Acad Sci USA 1997;94:9669–9673.

    PubMed  CAS  Google Scholar 

  120. Yang D, Kim KH, Phimister A, Girouard J, Ward T, Bachstetter A, Anderson KA, Kodavanti PRS, Stackman RW, Wisniewski AB, Klein S, Mervis R, Pessah IN, Lein PJ. PCBs alter dendritic plasticity coincident with disruptions of spatial learning in weanling rats. Env Health Perspect (submitted).

    Google Scholar 

  121. Kim KH, Inan SY, Berman RF, Pessah IN. Inhibitory deficits synergize hippocampus excitotoxicity of Ortho-substituted polychlorinated biphenyls and enhances seizure susceptibility. Toxicol Appl Pharmacol (submitted).

    Google Scholar 

  122. Kapfhammer JP. Cellular and molecular control of dendritic growth and development of cerebellar Purkinje cells. Prog Histochem Cytochem 2004;39:131–182.

    PubMed  Google Scholar 

  123. Cooke BM, Woolley CS. Gonadal hormone modulation of dendrites in the mammalian CNS. J Neurobiol 2005;64:34–46.

    PubMed  CAS  Google Scholar 

  124. Le Roux PD, Reh TA. Regional differences in glial-derived factors that promote dendritic outgrowth from mouse cortical neurons in vitro. J Neurosci 1994;14:4639–4655.

    PubMed  Google Scholar 

  125. Prochiantz A. Neuronal polarity: giving neurons heads and tails. Neuron 1995;15:743–746.

    PubMed  CAS  Google Scholar 

  126. Guo X, Metzler-Northrup J, Lein P, Rueger D, Higgins D. Leukemia inhibitory factor and ciliary neurotrophic factor regulate dendritic growth in cultures of rat sympathetic neurons. Brain Res Dev Brain Res 1997;104:101–110.

    PubMed  CAS  Google Scholar 

  127. Bauch H, Stier H, Schlosshauer B. Axonal versus dendritic outgrowth is differentially affected by radial glia in discrete layers of the retina. J Neurosci 1998;18:1774–1785.

    PubMed  CAS  Google Scholar 

  128. Blaser PF, Catsicas S, Clarke PG. Retrograde modulation of dendritic geometry in the vertebrate brain during development. Brain Res Dev Brain Res 1990;57:139–142.

    PubMed  CAS  Google Scholar 

  129. Andrews TJ. Autonomic nervous system as a model of neuronal aging: the role of target tissues and neurotrophic factors. Microsc Res Tech 1996;35:2–19.

    PubMed  CAS  Google Scholar 

  130. Brehmer A, Beleites B. Myenteric neurons with different projections have different dendritic tree patterns: a morphometric study in the pig ileum. J Auton Nerv Syst 1996;61:43–50.

    PubMed  CAS  Google Scholar 

  131. Cowen T, Gavazzi I. Plasticity in adult and ageing sympathetic neurons. Prog Neurobiol 1998;54:249–288.

    PubMed  CAS  Google Scholar 

  132. Higgins D, Burack M, Lein P, Banker G. Mechanisms of neuronal polarity. Curr Opin Neurobiol 1997;7:599–604.

    PubMed  CAS  Google Scholar 

  133. McAllister AK. Cellular and molecular mechanisms of dendrite growth. Cereb Cortex 2000;10:963–973.

    PubMed  CAS  Google Scholar 

  134. Herz J, Chen Y. Reelin, lipoprotein receptors and synaptic plasticity. Nat Rev Neurosci 2006;7:850–859.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular Bioscience, School of Veterinary Medicine and Center for Children’s Environmental Health Sciences and Disease Prevention, University of California, Davis, CA 95616, USA

    Isaac N. Pessah

Authors
  1. Isaac N. Pessah
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pamela J. Lein
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Humana Press, a part of Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Pessah, I.N., Lein, P.J. (2008). Evidence for Environmental Susceptibility in Autism. In: Autism. Current Clinical Neurology. Humana Press. https://doi.org/10.1007/978-1-60327-489-0_19

Download citation

  • DOI: https://doi.org/10.1007/978-1-60327-489-0_19

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-60327-488-3

  • Online ISBN: 978-1-60327-489-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation