BRAIN and NERVE－神経研究の進歩62巻9号

2010年09月発行

総説

自閉症スペクトラム障害の脳科学―社会性の障害に着目して

著者： 加藤進昌¹⁵ 山末英典²⁵ 渡辺慶一郎³ 神出誠一郎² 定松美幸⁴

所属機関： ¹昭和大学医学部精神医学教室 ²東京大学医学部附属病院精神神経科 ³東京大学保健センター ⁴奈良県立医科大学精神医学講座 ⁵独立行政法人科学技術振興機構CREST

ページ範囲：P.975 - P.986

文献概要

はじめに

　自閉症に関する脳科学的研究はいまや世界の神経科学の最重要課題になりつつある。それは社会性という人間が人間たる根幹の機能をサイエンスする格好のモデルを自閉症が提供しているからにほかならない。しかしながら，現在発表されているおびただしい研究を俯瞰するとき，臨床家としてはその研究対象ははたして臨床像を十分包含したものになっているかについて，一抹の不安を感じざるを得ない。そのために本稿では今一度臨床的事項を自分なりに整理して，研究的視点に立つときの問題意識を明らかにしたうえで，研究の流れを追いながら分野ごとに研究の進歩を紹介することにしたい。この研究の流れについても，筆者らが臨床的な観点から今後重要と考える方向性にある程度絞って紹介する。したがって本稿は研究のすべてを網羅したものではないことをお断りしておく。なお，より網羅的な研究の総説としては他に特集としてまとめたものを参考にしていただければ幸いである^1）。

参考文献

1) 岩波　明・加藤進昌（編): 特集・アスペルガー障害―最近の生物学的進歩. 精神科16 (1), 2010

2) Kanner L: Autistic disturbances of affective contact. Nervous Child 2: 217-250, 1943

3) Asperger H: Die ‘Autistischen Psychopathen' im Kindesalter. Archiv fur Psychiatrie und Nervenkrankheiten 117: 76-136, 1944

4) Wing L: Asperger's syndrome: a clinical account. Psychol Med 11: 115-129, 1981

5) Rodie P, Ingram JL, Tisdale B, Nelson S, Romano J: Embryological origin for autism: developmental anomalies of the cranial nerve motor nuclei. J Comp Neurol 370: 247-261, 1996

6) Andres C: Molecular genetics and animal models in autistic disorder. Brain Res Bull 57: 109-119, 2002

7) Allen GMR, Courchesne E: Cerebellar function in autism: functional magnetic resonance image activation during a simple motor task. Biol Psychiatry. 56: 269-278, 2004

8) Cheh MA, Millonig JH, Roselli LM, Ming X, Jacobsen E, et al: En2 knockout mice display neurobehavioral and neurochemical alterations relevant to autism spectrum disorder. Brain Res 1116: 166-176, 2006

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

10) Zhang A, Shen C, Ma SY, Ke Y, El Idrissi A: Altered expression of Autism-associated genes in the brain of Fragile X mouse model. Biochem Biophys Res Commun 379: 920-923, 2009

11) Hayashi ML, Rao BS., Seo JS, Choi HS, Dolan BM, et al: Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice. Proc Natl Acad Sci U S A 104: 11489-11494, 2007

12) McNaughton CH, Moon.J, Strawderman MS, Maclean KN, Evans J, et al: Evidence for social anxiety and impaired social cognition in a mouse model of fragile X syndrome. Behav Neurosci 122: 293-300, 2008

13) Moretti P, Levenson JM, Battaglia F, Atkinson R, Teague R, et al: Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome. J Neurosci 26: 319-327, 2006

14) Santangelo SL, Tsatsanis K: What is known about autism. Am J Pharmacogenom. 5: 71-92, 2005

15) Ehninger D, Han S, Shilyansky C, Zhou Y, Li W, et al: Reversal of learning deficits in a Tsc2 (＋/-) mouse model of tuberous sclerosis. Nat Med 14: 843-848, 2008

16) Waage-Baudet H, Lauder JM, Dehart DB, Kluckman K, Hiller S, et al: Abnormal serotonergic development in a mouse model for the Smith-Lemli-Opitz syndrome: implications for autism. Int J Devl Neurosci 21: 451-459, 2003

17) Wu S, Jia M, Ruan Y, Liu J, Guo Y, et al: Positive association of the oxytocin receptor gene (OXTR) with autism in the Chinese Han population. Biol Psychiatry 58: 74-77, 2005

18) McNamara IM, Borella AW, Bialowas LA, Whitaker-Azmitia PM: Further studies in the developmental hyperserotonemia model (DHS) of autism: Social, behavioral and peptide changes. Brain Res 1189: 203-214, 2007

19) Sadakata T, Furuichi T: Developmentally regulated Ca2＋-dependent activator protein for secretion 2 (CAPS2) is involved in BDNF secretion and is associated with autism susceptibility. Cerebellum 8: 312-322, 2009

20) Teitelbaum P: A proposed primate animal model of autism. Eur Child ＆ Adole Psychiat 12: 48-49, 2003

21) Narita N, Kato M, Tazoe M, Miyazaki K, Narita M, et al: 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, 2002

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

23) Schneider T, Przewtocki R: Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology 30: 80-89, 2005

24) Schneider T, ZiÓłkowska B, Gieryk A, Tyminska A, Przewłocki R: Prenatal exposure to valproic acid disturbs the enkephalinergic system functioning, basal hedonic tone, and emotional responses in an animal model of autism. Psychopharmacology (Berl) 193: 547-555, 2007

25) Rinaldi T, Perrodin C, Markram H: Hyper-connectivity and hyper-plasticity in the medial prefrontal cortex in the valproic Acid animal model of autism. Front Neural Circuits 2: 4, 2008

26) Libbey J, Sweeten TL, McMahon WM, Fujinami RS: Autistic disorder and viral infections. J Neurovirol 1: 1-10, 2005

27) Pletnikov M, Moran TH, Carbone KM: Borna disease virus infection of the neonatal rat: developmental brain injury model of autism spectrum disorders. Front Biosci 7: 593-607, 2002

28) Lancaster K, Dietz. DM, Moran TH, Pletnikov MV: Abnormal social behaviors in young and adult rats neonatally infected with Borna disease virus. Behav Brain Res 176: 141-148, 2007

29) Patterson P: Immune involvement in schizophrenia and autism: Etiology, pathology and animal models. Behav Brain Res 204: 313-321, 2009

30) Fatemi SH, Reutiman TJ, Folsom TD, Sidwell RW: The role of cerebellar genes in pathology of autism and schizophrenia. Cerebellum 7: 279-284, 2008

31) Sadamatsu M, Kanai H, Xu X, Liu Y, Kato N: Review of animal models for autism: implication of thyroid hormone. Congenit Anom (Kyoto) 46: 1-9, 2006

32) Wolterink G, Daenen LE, Dubbeldam S, Gerrits MA, van Rijn R, et al: Early amygdala damage in the rat as a model for neurodevelopmental psychopathological disorders. Eur Neuropsychopharmacol 11: 51-59, 2001

33) Daenen EW, Wolterink G, Gerrits, MA, Van Ree JM: The effects of neonatal lesions in the amygdala or ventral hippocampus on social behaviour later in life. Behav Brain Res 136: 571-582, 2002

34) Bernardet M, Crusio WE: Fmr1 KO mice as a possible model of autistic features. ScientificWorldJournal 26: 1164-1176, 2006

35) Markram K, Rinaldi T, La Mendola D, Sandi C, Markram H: Abnormal fear conditioning and amygdala processing in an animal model of autism. Neuropsychopharmacology 33: 901-912, 2008

36) Radyushkin K, Hammerschmidt K, Boretius S, Varoqueaux F, El-Kordi A, et al: Neuroligin-3-deficient mice: model of a monogenic heritable form of autism with an olfactory deficit. Genes Brain Behav 8: 416-425, 2209

37) Shi L, Fatemi SH, Sidwell RW, Patterson PH: Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J Neurosci 23: 297-302, 2003

38) Domes G, Heinrichs M, Michel A, Berger C, Herpertz SC: Oxytocin improves "mind-reading" in humans. Biol Psychiatry 61: 731-733, 2007

39) Modahl C, Green L, Fein D, Morris M, Waterhouse L, et al: Plasma oxytocin levels in autistic children. Biol Psychiatry 43: 270-277, 1998

40) Hollander E, Novotny S, Hanratty M, Yaffe R, DeCaria CM, et al: Oxytocin infusion reduces repetitive behaviors in adults with autistic and Asperger's disorders. Neuropsychopharmacology 28: 193-198, 2003

41) Wu S, Jia M, Ruan Y, Liu J, Guo Y, Shuang M, et al: Positive association of the oxytocin receptor gene (OXTR) with autism in the Chinese Han population. Biological Psychiatry 58: 74-77, 2005

42) Jacob S, Brune CW, Carter CS, Leventhal BL, Lord C, et al: Association of the oxytocin receptor gene (OXTR) in Caucasian children and adolescents with autism. Neurosci Lett 417: 6-9, 2007

43) Moy SS, Nadler JJ, Young NB, Perez A, Holloway LP, et al: Mouse behavioral tasks relevant to autism: phenotypes of 10 inbred strains. Behav Brain Res 176: 4-20, 2007

44) Insel TR, Young LJ: The neurobiology of attachment. Nat Rev Neurosci 2: 129-136, 2001

45) Williams JR, Insel TR, Harbaugh CR, Carter CS: Oxytocin administered centrally facilitates formation of a partner preference in female prairie voles (Microtus ochrogaster). J Neuroendocrinol 6: 247-250, 1994

46) Young LJ, Wang Z, Insel TR: Neuroendocrine bases of monogamy. Trends Neurosci 21: 71-75, 1998

47) Young LJ, Lim MM, Gingrich B, Insel TR: Cellular mechanisms of social attachment. Horm Behav 40: 133-138, 2001

48) Popik P, Vetulani J, van Ree JM: Low doses of oxytocin facilitate social recognition in rats. Psychopharmacology 106: 71-74, 1992

49) Benelli A, Bertolini A, Poggioli R, Menozzi B, Basaglia R, et al: Polymodal dose-response curve for oxytocin in the social recognition test. Neuropeptides 28: 251-255, 1995

50) Nishimori K, Young LJ, Guo Q, Wang Z, Insel TR, et al: Oxytocin is required for nursing but is not essential for parturition or reproductive behavior. Proc Natl Acad Sci U S A 93: 11699-11704, 1996

51) Young WS, Shepard E, Amico J, Hennighausen L, Wagner KU, et al: Deficiency in mouse oxytocin prevents milk ejection, but not fertility or parturition. J Neuroendocrinol 8: 847-853, 1996

52) Ferguson JN, Young LJ, Hearn EF, Matzuk MM, Insel TR, et al: Social amnesia in mice lacking the oxytocin gene. Nat Genet 25: 284-288, 2000

53) Takayanagi Y, Yoshida M, Bielsky IF, Ross HE, Kawamata M, et al: Pervasive social deficits, but normal parturition, in oxytocin receptor-deficient mice. Proc Natl Acad Sci U S A 102: 16096-16101, 2005

54) Jin D, Liu HX, Hirai H, Torashima T, Nagai T, et al: CD38 is critical for social behaviour by regulating oxytocin secretion. Nature 446: 41-45, 2007

55) 佐々木　司: 遺伝的要因　アスペルガー症候群―病因と臨床研究―　病因・病態の解明. 日本臨牀65: 443-448, 2007

56) Ronald A, Happe F, Bolton P, Butcher LM, Price TS, et al: Genetic heterogeneity between the three components of the autism spectrum: a twin study. J Am Acad Child Adolesc Psychiatry 45: 691-699, 2006

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

58) Ylisaukko-oja T, Nieminen-von Wendt T, Kempas E, Sarenius S, Varilo T, et al: Genome-wide scan for loci of Asperger syndrome. Molecular Psychiatry 9: 161-168, 2004

59) Abrahams BS, Geschwind DH: Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet 9: 341-355, 2008

60) Autism Genome Project Consortium; Szatmari P, Paterson AD, Zwaigenbaum L, Roberts W, Brian J, et al: Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 39: 319-328, 2007

61) Wang K, Zhang H, Ma D, Bucan M, Glessner JT, et al: Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459: 528-533, 2009

62) Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, et al: Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459: 569-573, 2009

63) Stone JL, Merriman B, Cantor RM, Yonan AL, Gilliam TC, et al: Evidence for sex-specific risk alleles in autism spectrum disorder. Am J Hum Genet 75: 1117-1123, 2004

64) Molloy CA, Keddache M, Martin LJ: Evidence for linkage on 21q and 7q in a subset of autism characterized by developmental regression. Molecular Psychiatry 10: 741-746, 2005

65) Alarcon M, Cantor RM, Liu J, Gilliam TC, Geschwind DH; Autism Genetic Research Exchange Consortium: Evidence for a language quantitative trait locus on chromosome 7q in multiplex autism families. Am J Hum Genet 70: 60-71, 2002

66) Ramoz N, Reichert JG, Smith CJ, Silverman JM, Bespalova IN,et al: Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism. Am J Psychiatry 161: 662-669, 2004

67) Segurado R, Conroy J, Meally E, Fitzgerald M, et al: Confirmation of association between autism and the mitochondrial aspartate/glutamate carrier SLC25A12 gene on chromosome 2q31. Am J Psychiatry 162: 2182-2184, 2005

68) Lepagnol-Bestel AM, Maussion G, Boda B, Cardona A, Iwayama Y, et al: SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects. Mol Psychiatry 13: 385-397, 2008

69) Wu S, Jia M, Ruan Y, Liu J, Guo Y, et al: Positive association of the oxytocin receptor gene (OXTR) with autism in the Chinese Han population. Biol Psychiatry 58: 74-77, 2005

70) Jacob S, Brune CW, Carter CS, Leventhal BL, Lord C, et al: Association of the oxytocin receptor gene (OXTR) in Caucasian children and adolescents with autism. Neurosci Lett 417: 6-9, 2007

71) Lerer E, Levi S, Salomon S, Darvasi A, Yirmiya N, et al: Association between the oxytocin receptor (OXTR) gene and autism: relationship to Vineland Adaptive Behavior Scales and cognition. Mol Psychiatry 13: 980-988, 2008

72) Yamasue H, Kuwabara H, Kawakubo Y, Kasai K: Oxytocin, sexually dimorphic features of the social brain, and autism. Psychiatry Clin Neurosci 63: 129-140, 2009

73) Jamain S, Betancur C, Quach H, Philippe A, Fellous M, et al. Paris Autism Research International Sibpair (PARIS) Study: Linkage and association of the glutamate receptor 6 gene with autism. Mol Psychiatry 7: 302-310, 2002

74) Shuang M, Liu J, Jia MX, Yang JZ, Wu SP, et al: Family-based association study between autism and glutamate receptor 6 gene in Chinese Han trios. Am J Med Genet B Neuropsychiatr Genet 131B: 48-50, 2004

75) Kim SA, Kim JH, Park M, Cho IH, Yoo HJ: Family-based association study between GRIK2 polymorphisms and autism spectrum disorders in the Korean trios. Neurosci Res 58: 332-335, 2007

76) Skaar DA, Shao Y, Haines JL, Stenger JE, Jaworski J, et al: Analysis of the RELN gene as a genetic risk factor for autism. Mol Psychiatry 10: 563-571, 2005

77) Serajee FJ, Zhong H, Mahbubul Huq AH: Association of Reelin gene polymorphisms with autism. Genomics 87: 75-83, 2006

78) Fatemi SH, Snow AV, Stary JM, raghi-Niknam M, Reutiman TJ, et al: Reelin signaling is impaired in autism. Biol Psychiatry 57: 777-787, 2005

79) Campbell DB, Sutcliffe JS, Ebert PJ, Militerni R, Bravaccio C, et al: A genetic variant that disrupts MET transcription is associated with autism. Proc Natl Acad Sci U S A 103: 16834-16839, 2006

80) Campbell DB, D'Oronzio R, Garbett K, Ebert PJ, Mirnics K, et al: Disruption of cerebral cortex MET signaling in autism spectrum disorder. Ann Neurol 62: 243-250, 2007

81) Pardo CA, Eberhart CG: The neurobiology of autism. Brain Pathol 17: 434-447, 2007

82) Arking DE, Cutler DJ, Brune CW, Teslovich TM, West K, et al: A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. Am J Hum Genet 82: 160-164, 2008

83) Alarcon M, Abrahams BS, Stone JL, Duvall JA, Perederiy JV, Bomar JM, et al: Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am J Hum Genet 82: 150-159, 2008

84) Vernes SC, Newbury DF, Abrahams BS, Winchester L, Nicod J, et al: A functional genetic link between distinct developmental language disorders. N Engl J Med 359: 2337-2345, 2008

85) Gharani N, Benayed R, Mancuso V, Brzustowicz LM, Millonig JH: Association of the homeobox transcription factor, ENGRAILED 2, 3, with autism spectrum disorder. Mol Psychiatry 9: 474-484, 2004

86) Benayed R, Gharani N, Rossman I, Mancuso V, Lazar G, et al: Support for the homeobox transcription factor gene ENGRAILED 2 as an autism spectrum disorder susceptibility locus. Am J Hum Genet 77: 851-868, 2005

87) Yang P, Lung FW, Jong YJ, Hsieh HY, Liang CL, et al: Association of the homeobox transcription factor gene ENGRAILED 2 with autistic disorder in Chinese children. Neuropsychobiology 57: 3-8, 2008

88) Cheh MA, Millonig JH, Roselli LM, Ming X, Jacobsen E et al: En2 knockout mice display neurobehavioral and neurochemical alterations relevant to autism spectrum disorder. Brain Res 1116: 166-176, 2006

89) Weiss LA, Kosova G, Delahanty RJ, Jiang L, Cook EH, et al: Variation in ITGB3 is associated with whole-blood serotonin level and autism susceptibility. Eur J Hum Genet 14: 923-931, 2006

90) Coutinho AM, Sousa I, Martins M, Correia C, Morgadinho T, et al: Evidence for epistasis between SLC6A4 and ITGB3 in autism etiology and in the determination of platelet serotonin levels. Hum Genet 121: 243-256, 2007

91) Persico AM, Bourgeron T: Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Trends Neurosci 29: 349-358, 2006

92) Jamain S, Quach H, Betancur C, Råstam M, Colineaux C, et al: Paris Autism Research International Sibpair Study. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet 34: 27-29, 2003

93) Kim HG, Kishikawa S, Higgins AW, Seong IS, Donovan DJ, et al: Disruption of neurexin 1 associated with autism spectrum disorder. Am J Hum Genet 82: 199-207, 2008

94) Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, et al: Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet 39: 25-27, 2007

95) Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E: Oxytocin increases trust in humans. Nature 435: 673-676, 2005

96) Guastella AJ, Mitchell PB, Mathews F: Oxytocin enhances the encoding of positive social memories in humans. Biol Psychiatry 64: 256-258, 2008

97) Guastella AJ, Mitchell PB, Dadds MR: Oxytocin increases gaze to the eye region of human faces. Biol Psychiatry 63: 3-5, 2008

98) Hollander E, Bartz J, Chaplin W, Phillips A, Sumner J, et al: Oxytocin increases retention of social cognition in autism. Biol Psychiatry 61: 498-503, 2007

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

100) Yamasue H, Ishijima M, Abe O, Sasaki T, Yamada H, et al: Neuroanatomy in monozygotic twins with Asperger disorder discordant for comorbid depression. Neurology 65: 491-492, 2005

101) Happe F, Ronald A, Plomin R: Time to give up on a single explanation for autism. Nat Neurosci 9: 1218-1220, 2006

102) Yamasue H, Abe O, Suga M, Yamada H, Rogers MA, et al: Sex-linked neuroanatomicalbBasis of human altruistic cooperativeness. Cereb Cortex 18: 2331-40, 2008

103) Baron-Cohen S: The extreme male brain theory of autism. Trends Cogn Sci 6: 248-254, 2002

104) 加藤進昌: ササッとわかる「大人のアスペルガー症候群」との接し方. 講談社, 東京, 2009