Autism is a heterogeneous behaviorally defined neurodevelopmental disorder. It is defined by the presence of marked social deficits, specific language abnormalities, and stereotyped repetitive patterns of behavior. Because of the variability in the behavioral phenotype of the disorder among patients, the term autism spectrum disorder has been established. In the first part of this review, we provide an overview of neuropathological findings from studies of autism postmortem brains and identify the cerebellum as one of the key brain regions that can play a role in the autism phenotype. We review research findings that indicate possible links between the environment and autism including the role of mercury and immune-related factors. Because both genes and environment can alter the structure of the developing brain in different ways, it is not surprising that there is heterogeneity in the behavioral and neuropathological phenotypes of autism spectrum disorders. Finally, we describe animal models of autism that occur following insertion of different autism-related genes and exposure to environmental factors, highlighting those models which exhibit both autism-like behavior and neuropathology. 1. Introduction Autism is a heterogeneous neurodevelopmental disorder with multiple causes and a great range in the severity of symptoms [1, 2]. As described by Kanner in 1943, individuals with autism have four core features: (i) impairments in reciprocal social interactions, (ii) an abnormal development in the use of language, (iii) repetitive and ritualized behaviors, and (iv) a narrow range of interests [3]. These symptoms range from mild to severe as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth edition (DSM-IV) [4] (Figure 1). In addition to the core features, people with autism often have comorbid neurological disorders such as mental retardation and epilepsy [5]. The prevalence of mental retardation with autism is ~60%, but in the broader autism spectrum disorders (ASDs), the number is closer to 30% [6]. Epilepsy has been long associated with autism although estimates of the occurrence of seizure disorder vary from 5% to 44% [7]. Anxiety and mood disorders are very common in autism [8]. There is also a substantial heterogeneity in the onset of autism. Impairments in some children manifest before 18 months of age; however, 25%–40% of children with autism initially demonstrate near normal development until 18–24 months, when they regress into autism that is generally indistinguishable from the early onset form of the disorder [8].
References
[1]
A. Bailey, W. Phillips, and M. Rutter, “Autism: towards an integration of clinical, genetic, neuropsychological, and neurobiological perspectives,” Journal of Child Psychology and Psychiatry and Allied Disciplines, vol. 37, no. 1, pp. 89–126, 1996.
[2]
D. G. Amaral, “The promise and the pitfalls of autism research: an introductory note for new autism researchers,” Brain Research, vol. 1380, pp. 3–9, 2011.
[3]
L. Kanner, “Autistic disturbances of affective contact,” Child's Nervous System, vol. 2, pp. 217–250, 1943.
[4]
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Washington, DC, USA, 4th edition, 2000.
[5]
J. McCarthy, C. Hemmings, E. Kravariti et al., “Challenging behavior and co-morbid psychopathology in adults with intellectual disability and autism spectrum disorders,” Research in Developmental Disabilities, vol. 31, no. 2, pp. 362–366, 2010.
[6]
E. Fombonne, “Autism and newborn encephalopathy,” Developmental Medicine and Child Neurology, vol. 48, no. 2, p. 84, 2006.
[7]
R. Tuchman and I. Rapin, “Epilepsy in autism,” Lancet Neurology, vol. 1, no. 6, pp. 352–358, 2002.
[8]
L. Lecavalier, “Behavioral and emotional problems in young people with pervasive developmental disorders: relative prevalence, effects of subject characteristics, and empirical classification,” Journal of Autism and Developmental Disorders, vol. 36, no. 8, pp. 1101–1114, 2006.
[9]
R. S. Williams, S. L. Hauser, and D. P. Purpura, “Autism and mental retardation. Neuropathologic studies performed in four retarded persons with autistic behavior,” Archives of Neurology, vol. 37, no. 12, pp. 749–753, 1980.
[10]
E. R. Ritvo, B. J. Freeman, and A. Mason-Brothers, “Concordance for the syndrome of autism in 40 pairs of afflicted twins,” American Journal of Psychiatry, vol. 142, no. 1, pp. 74–77, 1985.
[11]
A. Ronald, F. Happé, P. Bolton et al., “Genetic heterogeneity between the three components of the autism spectrum: a twin study,” Journal of the American Academy of Child and Adolescent Psychiatry, vol. 45, no. 6, pp. 691–699, 2006.
[12]
E. Fombonne, “The epidemiology of autism: a review,” Psychological Medicine, vol. 29, no. 4, pp. 769–786, 1999.
[13]
J. A. S. Vorstman, M. E. J. Morcus, S. N. Duijff et al., “The 22q11.2 deletion in children: high rate of autistic disorders and early onset of psychotic symptoms,” Journal of the American Academy of Child and Adolescent Psychiatry, vol. 45, no. 9, pp. 1104–1113, 2006.
[14]
P. Moretti and H. Y. Zoghbi, “MeCP2 dysfunction in Rett syndrome and related disorders,” Current Opinion in Genetics and Development, vol. 16, no. 3, pp. 276–281, 2006.
[15]
S. Jamain, H. Quach, C. Betancur et al., “Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism,” Nature Genetics, vol. 34, no. 1, pp. 27–29, 2003.
[16]
K. A. Strauss, E. G. Puffenberger, M. J. Huentelman et al., “Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2,” The New England Journal of Medicine, vol. 354, no. 13, pp. 1370–1377, 2006.
[17]
I. Lossifov, M. Ronemus, D. Levy, Z. Wang, et al., “De novo gene disruptions in children on the autistic spectrum,” Neuron, vol. 74, pp. 285–299, 2012.
[18]
S. C. Williams, “Genetics: searching for answers,” Nature, vol. 491, pp. S4–S6, 2012.
[19]
S. J. M. C. Palmen, H. Van Engeland, P. R. Hof, and C. Schmitz, “Neuropathological findings in autism,” Brain, vol. 127, no. 12, pp. 2572–2583, 2004.
[20]
P. L. Strick, R. P. Dum, and J. A. Fiez, “Cerebellum and nonmotor function,” Annual Review of Neuroscience, vol. 32, pp. 413–434, 2009.
[21]
G. Allen, “Cerebellum in Autism,” Clinical Neuropsychiatry, vol. 2, pp. 321–337, 2005.
[22]
G. Allen, “Cerebellar contributions to autism spectrum disorders,” Clinical Neuroscience Research, vol. 6, no. 3-4, pp. 195–207, 2006.
[23]
S. H. Fatemi, A. R. Halt, G. Realmuto et al., “Purkinje cell size is reduced in cerebellum of patients with autism,” Cellular and Molecular Neurobiology, vol. 22, no. 2, pp. 171–175, 2002.
[24]
W. E. Kaufmann, K. L. Cooper, S. H. Mostofsky et al., “Specificity of cerebellar vermian abnormalities in autism: a quantitative magnetic resonance imaging study,” Journal of Child Neurology, vol. 18, no. 7, pp. 463–470, 2003.
[25]
A. Bailey, P. Luthert, A. Dean et al., “A clinicopathological study of autism,” Brain, vol. 121, no. 5, pp. 889–905, 1998.
[26]
M. Bauman and T. L. Kemper, “Histoanatomic observations of the brain in early infantile autism,” Neurology, vol. 35, no. 6, pp. 866–874, 1985.
[27]
M. Lee, C. Martin-Ruiz, A. Graham et al., “Nicotinic receptor abnormalities in the cerebellar cortex in autism,” Brain, vol. 125, no. 7, pp. 1483–1495, 2002.
[28]
E. R. Whitney, T. L. Kemper, M. L. Bauman, D. L. Rosene, and G. J. Blatt, “Cerebellar Purkinje cells are reduced in a subpopulation of autistic brains: a stereological experiment using calbindin-D28k,” Cerebellum, vol. 7, no. 3, pp. 406–416, 2008.
[29]
J. Yip, J. J. Soghomonian, and G. J. Blatt, “Decreased GAD65 mRNA levels in select subpopulations of neurons in the cerebellar dentate nuclei in autism: an in situ hybridization study,” Autism Research, vol. 2, no. 1, pp. 50–59, 2009.
[30]
T. L. Kemper and M. Bauman, “Neuropathology of infantile Autism,” Journal of Neuropathology and Experimental Neurology, vol. 57, no. 7, pp. 645–652, 1998.
[31]
E. R. Ritvo, B. J. Freeman, and A. B. Scheibel, “Lower Purkinje cell counts in the cerebella of four autistic subjects: Initial findings of the UCLA-NSAC autopsy research report,” American Journal of Psychiatry, vol. 143, no. 7, pp. 862–866, 1986.
[32]
N. J. Minshew, “Neurologic apsects of autism,” in Handbook of Autism and Pervasive Developmental Disorders, vol. 1, pp. 473–524, John Wiley & Sons, 2005.
[33]
W. T. Thach, “A role for the cerebellum in learning movement coordination,” Neurobiology of Learning and Memory, vol. 70, no. 1-2, pp. 177–188, 1998.
[34]
E. Gowen and R. C. Miall, “The cerebellum and motor dysfunction in neuropsychiatric disorders,” Cerebellum, vol. 6, no. 3, pp. 268–279, 2007.
[35]
D. G. Amaral, C. M. Schumann, and C. W. Nordahl, “Neuroanatomy of autism,” Trends in Neurosciences, vol. 31, no. 3, pp. 137–145, 2008.
[36]
P. T. Tsai, C. Hull, Y. Chu, Y. E, et al., “Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice,” Nature, vol. 488, pp. 647–651, 2012.
[37]
C. M. Schumann and D. G. Amaral, “Stereological analysis of amygdala neuron number in autism,” Journal of Neuroscience, vol. 26, no. 29, pp. 7674–7679, 2006.
[38]
I. A. J. Van Kooten, S. J. M. C. Palmen, P. Von Cappeln et al., “Neurons in the fusiform gyrus are fewer and smaller in autism,” Brain, vol. 131, no. 4, pp. 987–999, 2008.
[39]
J. J. Hutsler and H. Zhang, “Increased dendritic spine densities on cortical projection neurons in autism spectrum disorders,” Brain Research, vol. 1309, pp. 83–94, 2010.
[40]
E. Courchesne, P. R. Mouton, M. E. Calhoun et al., “Neuron number and size in prefrontal cortex of children with autism,” Journal of the American Medical Association, vol. 306, no. 18, pp. 2001–2010, 2011.
[41]
M. Santos, N. Uppal, C. Butti et al., “von Economo neurons in autism: a stereologic study of the frontoinsular cortex in children,” Brain Research, vol. 1380, pp. 206–217, 2011.
[42]
S. Jacot-Descombes, N. Uppal, B. Wicinski et al., “Erratum to: decreased pyramidal neuron size in Brodmann areas 44 and 45 in patients with autism,” Acta Neuropathologica, vol. 124, no. 1, pp. 67–79, 2012.
[43]
R. Nicolson, T. J. DeVito, C. N. Vidal et al., “Detection and mapping of hippocampal abnormalities in autism,” Psychiatry Research, vol. 148, no. 1, pp. 11–21, 2006.
[44]
T. L. Kemper and M. L. Bauman, “The contribution of neuropathologic studies to the understanding of autism,” Neurologic Clinics, vol. 11, no. 1, pp. 175–187, 1993.
[45]
C. M. Schumann, C. C. Barnes, C. Lord, and E. Courchesne, “Amygdala enlargement in toddlers with autism related to severity of social and communication impairments,” Biological Psychiatry, vol. 66, no. 10, pp. 942–949, 2009.
[46]
C. M. Schumann, J. Hamstra, B. L. Goodlin-Jones et al., “The amygdala is enlarged in children but not adolescents with autism; the hippocampus is enlarged at all ages,” Journal of Neuroscience, vol. 24, no. 28, pp. 6392–6401, 2004.
[47]
E. H. Aylward, N. J. Minshew, G. Goldstein et al., “MRI volumes of amygdala and hippocampus in non-mentally retarded autistic adolescents and adults,” Neurology, vol. 53, no. 9, pp. 2145–2150, 1999.
[48]
R. A. Carper and E. Courchesne, “Localized enlargement of the frontal cortex in early autism,” Biological Psychiatry, vol. 57, no. 2, pp. 126–133, 2005.
[49]
E. Courchesne and K. Pierce, “Brain overgrowth in autism during a critical time in development: Implications for frontal pyramidal neuron and interneuron development and connectivity,” International Journal of Developmental Neuroscience, vol. 23, no. 2-3, pp. 153–170, 2005.
[50]
K. Suzuki, Y. Ouchi, K. Nakamura, et al., “Microglial activation in young adults with autism spectrum disorder,” JAMA Psychiatry, vol. 70, pp. 49–58, 2013.
[51]
H. C. Hazlett, M. D. Poe, G. Gerig, R. G. Smith, and J. Piven, “Cortical gray and white brain tissue volume in adolescents and adults with autism,” Biological Psychiatry, vol. 59, no. 1, pp. 1–6, 2006.
[52]
D. K. Shukla, B. Keehn, and R.-A. Müller, “Tract-specific analyses of diffusion tensor imaging show widespread white matter compromise in autism spectrum disorder,” Journal of Child Psychology and Psychiatry and Allied Disciplines, vol. 52, no. 3, pp. 286–295, 2011.
[53]
M. Noriuchi, Y. Kikuchi, T. Yoshiura et al., “Altered white matter fractional anisotropy and social impairment in children with autism spectrum disorder,” Brain Research, vol. 1362, pp. 141–149, 2010.
[54]
S. A. Irwin, B. Patel, M. Idupulapati, et al., “Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile-X syndrome: a quantitative examination,” American Journal of Medical Genetics, vol. 98, pp. 161–167, 2001.
[55]
A. Argyropoulos, K. L. Gilby, and E. Hill-Yardin, “Studying autism in rodent models: reconciling endophenotypes with comorbidities,” Frontiers in Human Neuroscience, vol. 7, p. 417, 2013.
[56]
W. Chonchaiya, J. Au, A. Schneider et al., “Increased prevalence of seizures in boys who were probands with the FMR1 premutation and co-morbid autism spectrum disorder,” Human Genetics, vol. 131, pp. 581–589, 2012.
[57]
D. B. Budimirovic and W. E. Kaufmann, “What can we learn about autism from studying fragile X syndrome?” Developmental Neuroscience, vol. 33, no. 5, pp. 379–394, 2011.
[58]
F. Tassone, N. S. Choudhary, B. Durbin-Johnson, et al., “Identification of expanded alleles of the FMR1 gene in the CHhildhood Autism Risks from Genes and Environment (CHARGE) study,” Journal of Autism Developmental Disorders, vol. 43, pp. 530–539, 2013.
[59]
M. Bernardet and W. E. Crusio, “Fmr1 KO mice as a possible model of autistic features,” The Scientific World Journal, vol. 6, pp. 1164–1176, 2006.
[60]
S. A. Hays, K. M. Huber, and J. R. Gibson, “Altered neocortical rhythmic activity states in Fmr1 KO mice are due to enhanced mGluR5 signaling and involve changes in excitatory circuitry,” Journal of Neuroscience, vol. 31, no. 40, pp. 14223–14234, 2011.
[61]
A. M. Peier, K. L. McIlwain, A. Kenneson, S. T. Warren, R. Paylor, and D. L. Nelson, “(Over)correction of FMR1 deficiency with YAC transgenics: behavioral and physical features,” Human Molecular Genetics, vol. 9, no. 8, pp. 1145–1159, 2000.
[62]
A. W. Grossman, G. M. Aldridge, K. J. Lee et al., “Developmental characteristics of dendritic spines in the dentate gyrus of Fmr1 knockout mice,” Brain Research, vol. 1355, pp. 221–227, 2010.
[63]
M. Chahrour and H. Y. Zoghbi, “The story of Rett syndrome: from clinic to neurobiology,” Neuron, vol. 56, no. 3, pp. 422–437, 2007.
[64]
S. S. Moy and J. J. Nadler, “Advances in behavioral genetics: mouse models of autism,” Molecular Psychiatry, vol. 13, no. 1, pp. 4–26, 2008.
[65]
M. D. Shahbazian, J. I. Young, L. A. Yuva-Paylor et al., “Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3,” Neuron, vol. 35, no. 2, pp. 243–254, 2002.
[66]
H.-T. Chao, H. Chen, R. C. Samaco et al., “Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes,” Nature, vol. 468, no. 7321, pp. 263–269, 2010.
[67]
T. Yang, M. B. Ramocki, J. L. Neul, J. L. W, et al., “Overexpression of methyl-CpG binding protein 2 impairs T(H)1 responses,” Science Translational Medicine, vol. 4, no. 163, 2012.
[68]
D. Comoletti, A. De Jaco, L. L. Jennings et al., “The Arg451Cys-neuroligin-3 mutation associated with autism reveals a defect in protein processing,” Journal of Neuroscience, vol. 24, no. 20, pp. 4889–4893, 2004.
[69]
K. Yanagi, T. Kaname, K. Wakui, et al., “Identification of four novel synonymous substitutions in the X-linked genes Neuroligin 3 and Neuroligin 4X in Japanese patients with autistic spectrum disorder,” Autism Research Treatment, vol. 2012, Article ID e724072, 5 pages, 2012.
[70]
K. M. Steinberg, D. Ramachandran, V. Patel, et al., “Identification of rare X-linked neuroligin variants by massively parallel sequencing in males with autism spectrum disorder,” Molecular Autism, vol. 3, pp. 1–8, 2012.
[71]
S. J. Baudouin, J. Gaudias, S. Gerharz, et al., “Shared synaptic pathophysiology in syndromic and nonsyndromic rodent models of autism,” Science, vol. 338, pp. 128–132, 2012.
[72]
J. R. W. Yates, “Tuberous sclerosis,” European Journal of Human Genetics, vol. 14, no. 10, pp. 1065–1073, 2006.
[73]
G. Ertan, S. Arulrajah, A. Tekes, L. Jordan, and T. A. G. M. Huisman, “Cerebellar abnormality in children and young adults with tuberous sclerosis complex: MR and diffusion weighted imaging findings,” Journal of Neuroradiology, vol. 37, no. 4, pp. 231–238, 2010.
[74]
A. M. Weber, J. C. Egelhoff, J. M. Mckellop, and D. N. Franz, “Autism and the cerebellum: evidence from tuberous sclerosis,” Journal of Autism and Developmental Disorders, vol. 30, no. 6, pp. 511–517, 2000.
[75]
T. J. Eluvathingal, M. E. Behen, H. T. Chugani et al., “Cerebellar lesions in tuberous sclerosis complex: neurobehavioral and neuroimaging correlates,” Journal of Child Neurology, vol. 21, no. 10, pp. 846–851, 2006.
[76]
S.-C. Chang, D. L. Pauls, C. Lange, R. Sasanfar, and S. L. Santangelo, “Common genetic variation in the GAD1 gene and the entire family of DLX homeobox genes and autism spectrum disorders,” American Journal of Medical Genetics B, vol. 156, no. 2, pp. 233–239, 2011.
[77]
T. Stühmer, S. A. Anderson, M. Ekker, and J. L. R. Rubenstein, “Ectopic expression of the Dlx genes induces glutamic acid decarboxylase and Dlx expression,” Development, vol. 129, no. 1, pp. 245–252, 2002.
[78]
S. Han, C. Tai, R. E. Westenbroek, et al., “Autistic-like behaviour in Scn1a+/- mice and rescue by enhanced GABA-mediated neurotransmission,” Nature, vol. 489, pp. 385–390, 2012.
[79]
F. J. Serajee, H. Zhong, and A. H. M. Mahbubul Huq, “Association of Reelin gene polymorphisms with autism,” Genomics, vol. 87, no. 1, pp. 75–83, 2006.
[80]
E. Bonora, K. S. Beyer, J. A. Lamb et al., “Analysis of reelin as a candidate gene for autism,” Molecular Psychiatry, vol. 8, no. 10, pp. 885–892, 2003.
[81]
A. Guidotti, J. Auta, J. M. Davis et al., “Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study,” Archives of General Psychiatry, vol. 57, no. 11, pp. 1061–1069, 2000.
[82]
T. Curran and G. D'Arcangelo, “Role of Reelin in the control of brain development,” Brain Research Reviews, vol. 26, no. 2-3, pp. 285–294, 1998.
[83]
N. Hadj-Sahraoui, F. Frédéric, N. Delhaye-Bouchaud, and J. Mariani, “Gender effect on Purkinje cell loss in the cerebellum of the heterozygous Reeler mouse,” Journal of Neurogenetics, vol. 11, no. 1-2, pp. 45–58, 1996.
[84]
N. Gharani, R. Benayed, V. Mancuso, L. M. Brzustowicz, and J. H. Millonig, “Association of the homeobox transcription factor, ENGRAILED 2, 3, with autism spectrum disorder,” Molecular Psychiatry, vol. 9, no. 5, pp. 474–484, 2004.
[85]
M. G. Butler, M. J. Dazouki, X.-P. Zhou et al., “Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations,” Journal of Medical Genetics, vol. 42, no. 4, pp. 318–321, 2005.
[86]
J. Zhou and L. F. Parada, “PTEN signaling in autism spectrum disorders,” Current Opinion in Neurobiology, vol. 22, pp. 873–879, 2012.
[87]
J. Zhou, J. Blundell, S. Ogawa et al., “Pharmacological inhibition of mTORCl suppresses anatomical, cellular, and behavioral abnormalities in neural-specific PTEN knock-out mice,” Journal of Neuroscience, vol. 29, no. 6, pp. 1773–1783, 2009.
[88]
X. C. Zhang, A. Piccini, M. P. Myers, et al., “Functional analysis of the protein phosphatase activity of PTEN,” Biochemistry Journal, vol. 444, pp. 457–464, 2012.
[89]
K. Stromland, V. Nordin, M. Miller, B. Akerstrom, and C. Gillberg, “Autism in thalidomide embryopathy: a population study,” Developmental Medicine and Child Neurology, vol. 36, no. 4, pp. 351–356, 1994.
[90]
D. Hranilovic, Z. Bujas-Petkovic, R. Vragovic, T. Vuk, K. Hock, and B. Jernej, “Hyperserotonemia in adults with autistic disorder,” Journal of Autism and Developmental Disorders, vol. 37, no. 10, pp. 1934–1940, 2007.
[91]
J. Piven, G. Tsai, E. Nehme, J. T. Coyle, G. A. Chase, and S. E. Folstein, “Platelet serotonin, a possible marker for familial autism,” Journal of Autism and Developmental Disorders, vol. 21, no. 1, pp. 51–59, 1991.
[92]
G. Williams, J. King, M. Cunningham, M. Stephan, B. Kerr, and J. H. Hersh, “Fetal valproate syndrome and autism: additional evidence of an association,” Developmental Medicine and Child Neurology, vol. 43, no. 3, pp. 202–206, 2001.
[93]
J. L. Ingram, S. M. Peckham, B. Tisdale, and P. M. Rodier, “Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism,” Neurotoxicology and Teratology, vol. 22, no. 3, pp. 319–324, 2000.
[94]
N. Narita, M. Kato, M. Tazoe, K. Miyazaki, M. Narita, and N. Okado, “Increased monoamine concentration in the brain and blood of fetal thalidomide- and valproic acid-exposed rat: putative animal models for autism,” Pediatric Research, vol. 52, no. 4, pp. 576–579, 2002.
[95]
P. Grandjean, E. Budtz-J？rgensen, R. F. White et al., “Methylmercury exposure biomarkers as indicators of neurotoxicity in children aged 7 years,” American Journal of Epidemiology, vol. 150, no. 3, pp. 301–305, 1999.
[96]
A. Falluel-Morel, K. Sokolowski, H. M. Sisti, X. Zhou, T. J. Shors, and E. DiCicco-Bloom, “Developmental mercury exposure elicits acute hippocampal cell death, reductions in neurogenesis, and severe learning deficits during puberty,” Journal of Neurochemistry, vol. 103, no. 5, pp. 1968–1981, 2007.
[97]
P. W. Davidson, D. A. Cory-Slechta, S. W. Thurston et al., “Fish consumption and prenatal methylmercury exposure: cognitive and behavioral outcomes in the main cohort at 17 years from the Seychelles child development study,” NeuroToxicology, vol. 32, no. 6, pp. 711–717, 2011.
[98]
A. Hviid, M. Stellfeld, J. Wohlfahrt, and M. Melbye, “Association between thimerosal-containing vaccine and Autism,” Journal of the American Medical Association, vol. 290, no. 13, pp. 1763–1766, 2003.
[99]
W. W. Thompson, C. Price, B. Goodson et al., “Early thimerosal exposure and neuropsychological outcomes at 7 to 10 years,” The New England Journal of Medicine, vol. 357, no. 13, pp. 1281–1292, 2007.
[100]
K. M. Madsen, M. B. Lauritsen, C. B. Pedersen et al., “Thimerosal and the occurrence of autism: negative ecological evidence from Danish population-based data,” Pediatrics, vol. 112, no. 3 I, pp. 604–606, 2003.
[101]
G. Delong, “A positive association found between autism prevalence and childhood vaccination uptake across the U.S. population,” Journal of Toxicology and Environmental Health A, vol. 74, no. 14, pp. 903–916, 2011.
[102]
J. P. Barile, G. P. Kuperminc, E. S. Weintraub, J. W. Mink, and W. W. Thompson, “Thimerosal exposure in early life and neuropsychological outcomes 7-10 years later,” Journal of Pediatric Psychology, vol. 37, no. 1, pp. 106–118, 2012.
[103]
R. Kurlan, M. P. McDermott, C. Deeley et al., “Prevalence of tics in schoolchildren and association with placement in special education,” Neurology, vol. 57, no. 8, pp. 1383–1388, 2001.
[104]
T. Verstraeten, R. L. Davis, F. DeStefano et al., “Safety of thimerosal-containing vaccines: a two-phased study of computerized health maintenance organization databases,” Pediatrics, vol. 112, no. 5, pp. 1039–1048, 2003.
[105]
A. E. Tozzi, P. Bisiacchi, V. Tarantino et al., “Neuropsychological performance 10 years after immunization in infancy with thimerosal-containing vaccines,” Pediatrics, vol. 123, no. 2, pp. 475–482, 2009.
[106]
H. ó. Atladóttir, P. Thorsen, L. ？stergaard et al., “Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders,” Journal of Autism and Developmental Disorders, vol. 40, no. 12, pp. 1423–1430, 2010.
[107]
L. Shi, S. E. P. Smith, N. Malkova, D. Tse, Y. Su, and P. H. Patterson, “Activation of the maternal immune system alters cerebellar development in the offspring,” Brain, Behavior, and Immunity, vol. 23, no. 1, pp. 116–123, 2009.
[108]
E. Y. Hsiao, S. W. McBride, J. Chow, et al., “Modeling an autism risk factor in mice leads to permanent immune dysregulation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 31, pp. 12776–12781, 2012.
[109]
P. A. Garay, E. Y. Hsiao, P. H. Patterson, and A. K. McAllister, “Maternal immune activation causes age- and region-specific changes in brain cytokines in offspring throughout development,” Brain Behavior and Immunity, vol. 31, pp. 54–68, 2013.
[110]
A. Kong, M. L. Frigge, G. Masson, G. S, et al., “Rate of de novo mutations and the importance of father's age to disease risk,” Nature, vol. 488, pp. 471–475, 2012.
[111]
B. D. Pearce, “Modeling the role of infections in the etiology of mental illness,” Clinical Neuroscience Research, vol. 3, no. 4-5, pp. 271–282, 2003.
[112]
T. Schneider, A. Roman, A. Basta-Kaim et al., “Gender-specific behavioral and immunological alterations in an animal model of autism induced by prenatal exposure to valproic acid,” Psychoneuroendocrinology, vol. 33, no. 6, pp. 728–740, 2008.
[113]
J. E. Libbey, T. L. Sweeten, W. M. McMahon, and R. S. Fujinami, “Autistic disorder and viral infections,” Journal of NeuroVirology, vol. 11, no. 1, pp. 1–10, 2005.
[114]
P. H. Patterson, “Maternal infection and immune involvement in autism,” Trends in Molecular Medicine, vol. 17, no. 7, pp. 389–394, 2011.
[115]
S. R. Goth, R. A. Chu, J. P. Gregg, G. Cherednichenko, and I. N. Pessah, “Uncoupling of ATP-mediated calcium signaling and dysregulated interleukin-6 secretion in dendritic cells by nanomolar thimerosal,” Environmental Health Perspectives, vol. 114, no. 7, pp. 1083–1091, 2006.
[116]
R. Pizzarelli and E. Cherubini, “Alterations of GABAergic signaling in autism spectrum disorders,” Neural Plasticity, vol. 2011, Article ID 297153, 2011.
[117]
A. Lerner, A. Bagic, E. A. Boudreau et al., “Neuroimaging of neuronal circuits involved in tic generation in patients with Tourette syndrome,” Neurology, vol. 68, no. 23, pp. 1979–1987, 2007.
[118]
E. Stern, D. A. Silbersweig, K.-Y. Chee et al., “Functional neuroanatomy of tics in Tourette syndrome,” Archives of General Psychiatry, vol. 57, no. 8, pp. 741–748, 2000.
