Neural Targets in the Study and Treatment of Social Cognition in Autism Spectrum Disorder

  • Arshya Vahabzadeh
  • Samantha M. Landino
  • Beate C. Finger
  • William A. CarlezonJr.
  • Christopher J. McDougleEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 228)


The purpose of this chapter is to present results from recent research on social cognition in autism spectrum disorder (ASD). The clinical phenomenology and neuroanatomical circuitry of ASD are first briefly described. The neuropharmacology of social cognition in animal models of ASD and humans is then addressed. Next, preclinical and clinical research on the neurohormone oxytocin is reviewed. This is followed by a presentation of results from preclinical and clinical studies on the excitatory amino acid glutamate. Finally, the role of neuroinflammation in ASD is addressed from the perspectives of preclinical neuroscience and research involving humans with ASD.


Autism Social cognition Neuropharmacology Preclinical Oxytocin Glutamate Neuroinflammation 



This work was supported, in part, by the Nancy Lurie Marks Family Foundation and the Robert and Donna Landreth Fund.


  1. Akhondzadeh S, Tajdar H, Mohammadi MR, Mohammadi M, Nouroozinejad GH, Shabstari OL, Ghelichnia HA (2008) A double-blind placebo controlled trial of piracetam added to risperidone in patients with autistic disorder. Child Psychiatry Hum Dev 39(3):237–245. doi: 10.1007/s10578-007-0084-3 PubMedCrossRefGoogle Scholar
  2. American Psychiatric Association APADSMTF (2013) Diagnostic and statistical manual of mental disorders: DSM-5. Available via Scholar
  3. Anagnostou E, Soorya L, Chaplin W, Bartz J, Halpern D, Wasserman S, Wang AT, Pepa L, Tanel N, Kushki A, Hollander E (2012) Intranasal oxytocin versus placebo in the treatment of adults with autism spectrum disorders: a randomized controlled trial. Mol Autism 3(1):16. doi: 10.1186/2040-2392-3-16 PubMedCentralPubMedCrossRefGoogle Scholar
  4. Andari E, Duhamel JR, Zalla T, Herbrecht E, Leboyer M, Sirigu A (2010) Promoting social behavior with oxytocin in high-functioning autism spectrum disorders. Proc Natl Acad Sci USA 107(9):4389–4394. doi: 10.1073/pnas.0910249107 PubMedCentralPubMedCrossRefGoogle Scholar
  5. Annaz D, Campbell R, Coleman M, Milne E, Swettenham J (2012) Young children with autism spectrum disorder do not preferentially attend to biological motion. J Autism Dev Disord 42(3):401–408PubMedCrossRefGoogle Scholar
  6. Asadabadi M, Mohammadi MR, Ghanizadeh A, Modabbernia A, Ashrafi M, Hassanzadeh E, Forghani S, Akhondzadeh S (2013) Celecoxib as adjunctive treatment to risperidone in children with autistic disorder: a randomized, double-blind, placebo-controlled trial. Psychopharmacology (Berl) 225(1):51–59. doi: 10.1007/s00213-012-2796-8 CrossRefGoogle Scholar
  7. Baio J, Centers for Disease Control and Prevention (2012) Prevalence of autism spectrum disorders: Autism and Developmental Disabilities Monitoring Network, 14 Sites, United States, 2008. MMWR Surveill Summ 61(3):1–19Google Scholar
  8. Bales KL, Perkeybile AM, Conley OG, Lee MH, Guoynes CD, Downing GM, Yun CR, Solomon M, Jacob S, Mendoza SP (2013) Chronic intranasal oxytocin causes long-term impairments in partner preference formation in male prairie voles. Biol Psychiatry 74(3):180–188. doi: 10.1016/j.biopsych.2012.08.025 PubMedCentralPubMedCrossRefGoogle Scholar
  9. Bear MF, Huber KM, Warren ST (2004) The mGluR theory of fragile X mental retardation. Trends Neurosci 27(7):370–377. doi: 10.1016/j.tins.2004.04.009 PubMedCrossRefGoogle Scholar
  10. Becker JA, Clesse D, Spiegelhalter C, Schwab Y, Le Merrer J, Kieffer BL (2014) Autistic-like syndrome in mu opioid receptor null mice is relieved by facilitated mGluR4 activity. Neuropsychopharmacology 39(9):2049–2060. doi: 10.1038/npp.2014.59 PubMedCrossRefGoogle Scholar
  11. Bernardi S, Anagnostou E, Shen J, Kolevzon A, Buxbaum JD, Hollander E, Hof PR, Fan J (2011) In vivo 1H-magnetic resonance spectroscopy study of the attentional networks in autism. Brain Res 1380:198–205. doi: 10.1016/j.brainres.2010.12.057 PubMedCentralPubMedCrossRefGoogle Scholar
  12. Bielsky IF, Young LJ (2004) Oxytocin, vasopressin, and social recognition in mammals. Peptides 25(9):1565–1574. doi: 10.1016/j.peptides.2004.05.019 PubMedCrossRefGoogle Scholar
  13. Blaylock RL, Strunecka A (2009) Immune-glutamatergic dysfunction as a central mechanism of the autism spectrum disorders. Curr Med Chem 16(2):157–170PubMedCrossRefGoogle Scholar
  14. Boraston ZL, Corden B, Miles LK, Skuse DH, Blakemore SJ (2008) Brief report: perception of genuine and posed smiles by individuals with autism. J Autism Dev Disord 38(3):574–580. doi: 10.1007/s10803-007-0421-1 PubMedCrossRefGoogle Scholar
  15. Boris M, Goldblatt A, Edelson SM (2005) Improvement in children with autism treated with intravenous gamma globulin. J Nutr Environ Med 15(4):169–176CrossRefGoogle Scholar
  16. Borrell J, Vela JM, Arevalo-Martin A, Molina-Holgado E, Guaza C (2002) Prenatal immune challenge disrupts sensorimotor gating in adult rats. Implications for the etiopathogenesis of schizophrenia. Neuropsychopharmacology 26(2):204–215. doi: 10.1016/S0893-133X(01)00360-8 PubMedCrossRefGoogle Scholar
  17. Buitelaar JK, van Engeland H, van Ree JM, de Wied D (1990) Behavioral effects of Org 2766, a synthetic analog of the adrenocorticotrophic hormone (4-9), in 14 outpatient autistic children. J Autism Dev Disord 20(4):467–478PubMedCrossRefGoogle Scholar
  18. Buitelaar JK, van Engeland H, de Kogel K, de Vries H, van Hooff J, van Ree J (1992a) The adrenocorticotrophic hormone (4-9) analog ORG 2766 benefits autistic children: report on a second controlled clinical trial. J Am Acad Child Adolesc Psychiatry 31(6):1149–1156PubMedCrossRefGoogle Scholar
  19. Buitelaar JK, van Engeland H, de Kogel KH, de Vries H, van Hooff JA, van Ree JM (1992b) The use of adrenocorticotrophic hormone (4-9) analog ORG 2766 in autistic children: effects on the organization of behavior. Biol Psychiatry 31(11):1119–1129PubMedCrossRefGoogle Scholar
  20. Carlson GC (2012) Glutamate receptor dysfunction and drug targets across models of autism spectrum disorders. Pharmacol Biochem Behav 100(4):850–854. doi: 10.1016/j.pbb.2011.02.003 PubMedCentralPubMedCrossRefGoogle Scholar
  21. Carlsson ML (1998) Hypothesis: is infantile autism a hypoglutamatergic disorder? Relevance of glutamate—serotonin interactions for pharmacotherapy. J Neural Transm 105(4–5):525–535PubMedCrossRefGoogle Scholar
  22. Carroll LS, Owen MJ (2009) Genetic overlap between autism, schizophrenia and bipolar disorder. Genome Med 1(10):102–102.7. doi: 10.1186/gm102 PubMedCentralPubMedCrossRefGoogle Scholar
  23. Cheung C, Yu K, Fung G, Leung M, Wong C, Li Q, Sham P, Chua S, McAlonan G (2010) Autistic disorders and schizophrenia: related or remote? An anatomical likelihood estimation. PLoS One 5(8):e12233PubMedCentralPubMedCrossRefGoogle Scholar
  24. Chez ML, Loeffel M, Buchanan CP, Field-Chez M (1998) Pulse high dose steroids as combination therapy with valproic acid in epileptic aphasia patients with pervasive developmental delay or autism. Ann Neurol 44(3):53–59. doi: 10.1002/ana.410440345 Google Scholar
  25. Chez MG, Burton Q, Dowling T, Chang M, Khanna P, Kramer C (2007) Memantine as adjunctive therapy in children diagnosed with autistic spectrum disorders: an observation of initial clinical response and maintenance tolerability. J Child Neurol 22(5):574–579. doi: 10.1177/0883073807302611 PubMedCrossRefGoogle Scholar
  26. Crespi B, Stead P, Elliot M (2010) Comparative genomics of autism and schizophrenia. Proc Natl Acad Sci 107(suppl 1):1736–1741PubMedCentralPubMedCrossRefGoogle Scholar
  27. Dalton KM, Nacewicz BM, Johnstone T, Schaefer HS, Gernsbacher MA, Goldsmith HH, Alexander AL, Davidson RJ (2005) Gaze fixation and the neural circuitry of face processing in autism. Nat Neurosci 8(4):519–526. doi: 10.1038/nn1421 PubMedCentralPubMedGoogle Scholar
  28. DelGiudice-Asch G, Simon L, Schmeidler J, Cunningham-Rundles C, Hollander E (1999) Brief report: a pilot open clinical trial of intravenous immunoglobulin in childhood autism. J Autism Dev Disord 29(2):157–160PubMedCrossRefGoogle Scholar
  29. DeVito TJ, Drost DJ, Neufeld RW, Rajakumar N, Pavlosky W, Williamson P, Nicolson R (2007) Evidence for cortical dysfunction in autism: a proton magnetic resonance spectroscopic imaging study. Biol Psychiatry 61(4):465–473. doi: 10.1016/j.biopsych.2006.07.022 PubMedCrossRefGoogle Scholar
  30. Domes G, Kumbier E, Heinrichs M, Herpertz SC (2013) Oxytocin promotes facial emotion recognition and amygdala reactivity in adults with asperger syndrome. Neuropsychopharmacology 39(3):698–706. doi: 10.1038/npp.2013.254 PubMedCentralPubMedCrossRefGoogle Scholar
  31. Donaldson ZR, Young LJ (2008) Oxytocin, vasopressin, and the neurogenetics of sociality. Science 322(5903):900–904. doi: 10.1126/science.1158668 PubMedCrossRefGoogle Scholar
  32. Erickson CA, Posey DJ, Stigler KA, Mullett J, Katschke AR, McDougle CJ (2007) A retrospective study of memantine in children and adolescents with pervasive developmental disorders. Psychopharmacology (Berl) 191(1):141–147. doi: 10.1007/s00213-006-0518-9 CrossRefGoogle Scholar
  33. Evins AE, Amico E, Posever TA, Toker R, Goff DC (2002) d-Cycloserine added to risperidone in patients with primary negative symptoms of schizophrenia. Schizophr Res 56(1–2):19–23PubMedCrossRefGoogle Scholar
  34. Ey E, Leblond CS, Bourgeron T (2011) Behavioral profiles of mouse models for autism spectrum disorders. Autism Res 4(1):5–16. doi: 10.1002/aur.175 PubMedCrossRefGoogle Scholar
  35. Farroni T, Csibra G, Simion F, Johnson MH (2002) Eye contact detection in humans from birth. Proc Natl Acad Sci U S A 99(14):9602–9605. doi: 10.1073/pnas.152159999 PubMedCentralPubMedCrossRefGoogle Scholar
  36. Ferguson JN, Young LJ, Hearn EF, Matzuk MM, Insel TR, Winslow JT (2000) Social amnesia in mice lacking the oxytocin gene. Nat Genet 25(3):284–288. doi: 10.1038/77040 PubMedCrossRefGoogle Scholar
  37. Ferguson JN, Aldag JM, Insel TR, Young LJ (2001) Oxytocin in the medial amygdala is essential for social recognition in the mouse. J Neurosci 21(20):8278–8285PubMedGoogle Scholar
  38. Friedman SD, Shaw DW, Artru AA, Dawson G, Petropoulos H, Dager SR (2006) Gray and white matter brain chemistry in young children with autism. Arch Gen Psychiatry 63(7):786–794. doi: 10.1001/archpsyc.63.7.786 PubMedCrossRefGoogle Scholar
  39. Frith CD (2008) Social cognition. Philos Trans R Soc Lond B Biol Sci 363(1499):2033–2039. doi: 10.1098/rstb.2008.0005 PubMedCentralPubMedCrossRefGoogle Scholar
  40. Gantois I, Pop AS, de Esch CE, Buijsen RA, Pooters T, Gomez-Mancilla B, Gasparini F, Oostra BA, D'Hooge R, Willemsen R (2013) Chronic administration of AFQ056/Mavoglurant restores social behaviour in Fmr1 knockout mice. Behav Brain Res 239:72–79. doi: 10.1016/j.bbr.2012.10.059 PubMedCrossRefGoogle Scholar
  41. Garay PA, Hsiao EY, Patterson PH, McAllister AK (2013) Maternal immune activation causes age- and region-specific changes in brain cytokines in offspring throughout development. Brain Behav Immun 31:54–68. doi: 10.1016/j.bbi.2012.07.008 PubMedCentralPubMedCrossRefGoogle Scholar
  42. Ghaleiha A, Asadabadi M, Mohammadi MR, Shahei M, Tabrizi M, Hajiaghaee R, Hassanzadeh E, Akhondzadeh S (2013) Memantine as adjunctive treatment to risperidone in children with autistic disorder: a randomized, double-blind, placebo-controlled trial. Int J Neuropsychopharmacol 16(4):783–789. doi: 10.1017/S1461145712000880 PubMedCrossRefGoogle Scholar
  43. Goff DC, Cather C, Gottlieb JD, Evins AE, Walsh J, Raeke L, Otto MW, Schoenfeld D, Green MF (2008) Once-weekly d-cycloserine effects on negative symptoms and cognition in schizophrenia: an exploratory study. Schizophr Res 106(2–3):320–327. doi: 10.1016/j.schres.2008.08.012 PubMedCentralPubMedCrossRefGoogle Scholar
  44. Gordon I, Vander Wyk BC, Bennett RH, Cordeaux C, Lucas MV, Eilbott JA, Zagoory-Sharon O, Leckman JF, Feldman R, Pelphrey KA (2013) Oxytocin enhances brain function in children with autism. Proc Natl Acad Sci USA 110(52):20953–20958. doi: 10.1073/pnas.1312857110 PubMedCentralPubMedCrossRefGoogle Scholar
  45. Gotts SJ, Simmons WK, Milbury LA, Wallace GL, Cox RW, Martin A (2012) Fractionation of social brain circuits in autism spectrum disorders. Brain 135(Pt 9):2711–2725. doi: 10.1093/brain/aws160 PubMedCentralPubMedCrossRefGoogle Scholar
  46. Grice SJ, Halit H, Farroni T, Baron-Cohen S, Bolton P, Johnson MH (2005) Neural correlates of eye-gaze detection in young children with autism. Cortex 41(3):342–353PubMedCrossRefGoogle Scholar
  47. Guastella AJ, Mitchell PB, Dadds MR (2008) Oxytocin increases gaze to the eye region of human faces. Biol Psychiatry 63(1):3–5. doi: 10.1016/j.biopsych.2007.06.026 PubMedCrossRefGoogle Scholar
  48. Guastella AJ, Einfeld SL, Gray KM, Rinehart NJ, Tonge BJ, Lambert TJ, Hickie IB (2010) Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders. Biol Psychiatry 67(7):692–694. doi: 10.1016/j.biopsych.2009.09.020 PubMedCrossRefGoogle Scholar
  49. Gupta S, Aggarwal S, Heads C (1996) Dysregulated immune system in children with autism: beneficial effects of intravenous immune globulin on autistic characteristics. J Autism Dev Disord 26(4):439–452PubMedCrossRefGoogle Scholar
  50. Haith M, Bergman T, Moore M (1977) Eye contact and face scanning in early infancy. Science 198(4319):853–855. doi: 10.1126/science.918670 PubMedCrossRefGoogle Scholar
  51. Hamza RT, Hewedi DH, Ismail MA (2010) Basal and adrenocorticotropic hormone stimulated plasma cortisol levels among Egyptian autistic children: relation to disease severity. Ital J Pediatr 36:71. doi: 10.1186/1824-7288-36-71 PubMedCentralPubMedCrossRefGoogle Scholar
  52. Handen BL, Melmed RD, Hansen RL, Aman MG, Burnham DL, Bruss JB, McDougle CJ (2009) A double-blind, placebo-controlled trial of oral human immunoglobulin for gastrointestinal dysfunction in children with autistic disorder. J Autism Dev Disord 39(5):796–805. doi: 10.1007/s10803-008-0687-y PubMedCrossRefGoogle Scholar
  53. Harada M, Taki MM, Nose A, Kubo H, Mori K, Nishitani H, Matsuda T (2011) Non-invasive evaluation of the GABAergic/glutamatergic system in autistic patients observed by MEGA-editing proton MR spectroscopy using a clinical 3 T instrument. J Autism Dev Disord 41(4):447–454. doi: 10.1007/s10803-010-1065-0 PubMedCrossRefGoogle Scholar
  54. Hardan AY, Minshew NJ, Melhem NM, Srihari S, Jo B, Bansal R, Keshavan MS, Stanley JA (2008) An MRI and proton spectroscopy study of the thalamus in children with autism. Psychiatry Res 163(2):97–105. doi: 10.1016/j.pscychresns.2007.12.002 PubMedCentralPubMedCrossRefGoogle Scholar
  55. Haxby JV, Hoffman EA, Gobbini MI (2002) Human neural systems for face recognition and social communication. Biol Psychiatry 51(1):59–67PubMedCrossRefGoogle Scholar
  56. Heresco-Levy U, Javitt DC (2004) Comparative effects of glycine and d-cycloserine on persistent negative symptoms in schizophrenia: a retrospective analysis. Schizophr Res 66(2–3):89–96. doi: 10.1016/S0920-9964(03)00129-4 PubMedCrossRefGoogle Scholar
  57. Heuer L, Ashwood P, Schauer J, Goines P, Krakowiak P, Hertz-Picciotto I, Hansen R, Croen LA, Pessah IN, Van de Water J (2008) Reduced levels of immunoglobulin in children with autism correlates with behavioral symptoms. Autism Res 1(5):275–283. doi: 10.1002/aur.42 PubMedCentralPubMedCrossRefGoogle Scholar
  58. Higashida H, Yokoyama S, Munesue T, Kikuchi M, Minabe Y, Lopatina O (2011) CD38 gene knockout juvenile mice: a model of oxytocin signal defects in autism. Biol Pharm Bull 34(9):1369–1372PubMedCrossRefGoogle Scholar
  59. Higashida H, Yokoyama S, Kikuchi M, Munesue T (2012) CD38 and its role in oxytocin secretion and social behavior. Horm Behav 61(3):351–358. doi: 10.1016/j.yhbeh.2011.12.011 PubMedCrossRefGoogle Scholar
  60. Hollander E, Novotny S, Hanratty M, Yaffe R, DeCaria CM, Aronowitz BR, Mosovich S (2003) Oxytocin infusion reduces repetitive behaviors in adults with autistic and Asperger’s disorders. Neuropsychopharmacology 28(1):193–198. doi: 10.1038/sj.npp.1300021 PubMedCrossRefGoogle Scholar
  61. Hollander E, Bartz J, Chaplin W, Phillips A, Sumner J, Soorya L, Anagnostou E, Wasserman S (2007) Oxytocin increases retention of social cognition in autism. Biol Psychiatry 61(4):498–503. doi: 10.1016/j.biopsych.2006.05.030 PubMedCrossRefGoogle Scholar
  62. Horder J, Lavender T, Mendez MA, O'Gorman R, Daly E, Craig MC, Lythgoe DJ, Barker GJ, Murphy DG (2013) Reduced subcortical glutamate/glutamine in adults with autism spectrum disorders: a [(1)H]MRS study. Transl Psychiatry 3:e279. doi: 10.1038/tp.2013.53 PubMedCentralPubMedCrossRefGoogle Scholar
  63. Huang H, Michetti C, Busnelli M, Manago F, Sannino S, Scheggia D, Giancardo L, Sona D, Murino V, Chini B, Scattoni ML, Papaleo F (2014) Chronic and acute intranasal oxytocin produce divergent social effects in mice. Neuropsychopharmacology 39(5):1102–1114. doi: 10.1038/npp.2013.310 PubMedCentralPubMedCrossRefGoogle Scholar
  64. Jin D, Liu HX, Hirai H, Torashima T, Nagai T, Lopatina O, Shnayder NA, Yamada K, Noda M, Seike T, Fujita K, Takasawa S, Yokoyama S, Koizumi K, Shiraishi Y, Tanaka S, Hashii M, Yoshihara T, Higashida K, Islam MS, Yamada N, Hayashi K, Noguchi N, Kato I, Okamoto H, Matsushima A, Salmina A, Munesue T, Shimizu N, Mochida S, Asano M, Higashida H (2007) CD38 is critical for social behaviour by regulating oxytocin secretion. Nature 446(7131):41–45. doi: 10.1038/nature05526 PubMedCrossRefGoogle Scholar
  65. Jones W, Carr K, Klin A (2008) Absence of preferential looking to the eyes of approaching adults predicts level of social disability in 2-year-old toddlers with autism spectrum disorder. Arch Gen Psychiatry 65(8):946–954. doi: 10.1001/archpsyc.65.8.946 PubMedCrossRefGoogle Scholar
  66. Just MA, Keller TA, Malave VL, Kana RK, Varma S (2012) Autism as a neural systems disorder: a theory of frontal-posterior underconnectivity. Neurosci Biobehav Rev 36(4):1292–1313. doi: 10.1016/j.neubiorev.2012.02.007 PubMedCentralPubMedCrossRefGoogle Scholar
  67. Kannan S, Saadani-Makki F, Muzik O, Chakraborty P, Mangner TJ, Janisse J, Romero R, Chugani DC (2007) Microglial activation in perinatal rabbit brain induced by intrauterine inflammation: detection with 11C-(R)-PK11195 and small-animal PET. J Nucl Med 48(6):946–954. doi: 10.2967/jnumed.106.038539 PubMedCrossRefGoogle Scholar
  68. Kaytor MD, Orr HT (2001) RNA targets of the fragile X protein. Cell 107(5):555–557PubMedCrossRefGoogle Scholar
  69. Kenna HA, Poon AW, de los Angeles CP, Koran LM (2011) Psychiatric complications of treatment with corticosteroids: review with case report. Psychiatry Clin Neurosci 65(6):549–560. doi: 10.1111/j.1440-1819.2011.02260.x PubMedCrossRefGoogle Scholar
  70. Kimura M, Toth LA, Agostini H, Cady AB, Majde JA, Krueger JM (1994) Comparison of acute phase responses induced in rabbits by lipopolysaccharide and double-stranded RNA. Am J Physiol 267(6 Pt 2):R1596–R1605PubMedGoogle Scholar
  71. Kleinhans NM, Richards T, Johnson LC, Weaver KE, Greenson J, Dawson G, Aylward E (2011) fMRI evidence of neural abnormalities in the subcortical face processing system in ASD. Neuroimage 54(1):697–704. doi: 10.1016/j.neuroimage.2010.07.037 PubMedCentralPubMedCrossRefGoogle Scholar
  72. Klin A, Sparrow SS, de Bildt A, Cicchetti DV, Cohen DJ, Volkmar FR (1999) A normed study of face recognition in autism and related disorders. J Autism Dev Disord 29(6):499–508PubMedCrossRefGoogle Scholar
  73. Klin A, Lin DJ, Gorrindo P, Ramsay G, Jones W (2009) Two-year-olds with autism orient to non-social contingencies rather than biological motion. Nature 459(7244):257–261PubMedCentralPubMedCrossRefGoogle Scholar
  74. Lim MM, Bielsky IF, Young LJ (2005) Neuropeptides and the social brain: potential rodent models of autism. Int J Dev Neurosci 23(2–3):235–243. doi: 10.1016/j.ijdevneu.2004.05.006 PubMedCrossRefGoogle Scholar
  75. Liu HX, Lopatina O, Higashida C, Tsuji T, Kato I, Takasawa S, Okamoto H, Yokoyama S, Higashida H (2008) Locomotor activity, ultrasonic vocalization and oxytocin levels in infant CD38 knockout mice. Neurosci Lett 448(1):67–70. doi: 10.1016/j.neulet.2008.09.084 PubMedCrossRefGoogle Scholar
  76. Lukas M, Neumann ID (2013) Oxytocin and vasopressin in rodent behaviors related to social dysfunctions in autism spectrum disorders. Behav Brain Res 251:85–94. doi: 10.1016/j.bbr.2012.08.011 PubMedCrossRefGoogle Scholar
  77. Lynch CJ, Uddin LQ, Supekar K, Khouzam A, Phillips J, Menon V (2013) Default mode network in childhood autism: posteromedial cortex heterogeneity and relationship with social deficits. Biol Psychiatry 74(3):212–219. doi: 10.1016/j.biopsych.2012.12.013 PubMedCentralPubMedCrossRefGoogle Scholar
  78. Malkova NV, Yu CZ, Hsiao EY, Moore MJ, Patterson PH (2012) Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain Behav Immun 26(4):607–616. doi: 10.1016/j.bbi.2012.01.011 PubMedCentralPubMedCrossRefGoogle Scholar
  79. Marinovic-Curin J, Marinovic-Terzic I, Bujas-Petkovic Z, Zekan L, Skrabic V, Dogas Z, Terzic J (2008) Slower cortisol response during ACTH stimulation test in autistic children. Eur Child Adolesc Psychiatry 17(1):39–43. doi: 10.1007/s00787-007-0632-1 PubMedCrossRefGoogle Scholar
  80. Markram K, Rinaldi T, La Mendola D, Sandi C, Markram H (2008) Abnormal fear conditioning and amygdala processing in an animal model of autism. Neuropsychopharmacology 33(4):901–912. doi: 10.1038/sj.npp.1301453 PubMedCrossRefGoogle Scholar
  81. McCall C, Singer T (2012) The animal and human neuroendocrinology of social cognition, motivation and behavior. Nat Neurosci 15(5):681–688. doi: 10.1038/nn.3084 PubMedCrossRefGoogle Scholar
  82. McDougle CJ, Carlezon WA Jr (2013) Neuroinflammation and autism: toward mechanisms and treatments. Neuropsychopharmacology 38(1):241–242. doi: 10.1038/npp.2012.174 PubMedCentralPubMedCrossRefGoogle Scholar
  83. Mens WB, Witter A, van Wimersma Greidanus TB (1983) Penetration of neurohypophyseal hormones from plasma into cerebrospinal fluid (CSF): half-times of disappearance of these neuropeptides from CSF. Brain Res 262(1):143–149PubMedCrossRefGoogle Scholar
  84. Meyer U, Nyffeler M, Engler A, Urwyler A, Schedlowski M, Knuesel I, Yee BK, Feldon J (2006) The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology. J Neurosci 26(18):4752–4762. doi:10.1523/JNEUROSCI. 0099-06.2006PubMedCrossRefGoogle Scholar
  85. Meyer U, Murray PJ, Urwyler A, Yee BK, Schedlowski M, Feldon J (2008) Adult behavioral and pharmacological dysfunctions following disruption of the fetal brain balance between pro-inflammatory and IL-10-mediated anti-inflammatory signaling. Mol Psychiatry 13(2):208–221. doi: 10.1038/ PubMedCrossRefGoogle Scholar
  86. Monk CS, Weng SJ, Wiggins JL, Kurapati N, Louro HM, Carrasco M, Maslowsky J, Risi S, Lord C (2010) Neural circuitry of emotional face processing in autism spectrum disorders. J Psychiatry Neurosci 35(2):105–114PubMedCentralPubMedCrossRefGoogle Scholar
  87. Mordekar SR, Prendergast M, Chattopadhyay AK, Baxter PS (2009) Corticosteroid treatment of behaviour, language and motor regression in childhood disintegrative disorder. Eur J Paediatr Neurol 13(4):367–369. doi: 10.1016/j.ejpn.2008.06.001 PubMedCrossRefGoogle Scholar
  88. Mundy P, Sullivan L, Mastergeorge AM (2009) A parallel and distributed-processing model of joint attention, social cognition and autism. Autism Res 2(1):2–21. doi: 10.1002/aur.61 PubMedCentralPubMedCrossRefGoogle Scholar
  89. Niederhofer H (2007) Glutamate antagonists seem to be slightly effective in psychopharmacologic treatment of autism. J Clin Psychopharmacol 27(3):317–318. doi: 10.1097/ PubMedCrossRefGoogle Scholar
  90. O’Connor EC, Bariselli S, Bellone C (2014) Synaptic basis of social dysfunction: a focus on postsynaptic proteins linking group-I mGluRs with AMPARs and NMDARs. Eur J Neurosci 39(7):1114–1129. doi: 10.1111/ejn.12510 PubMedCrossRefGoogle Scholar
  91. Onore CE, Schwartzer JJ, Careaga M, Berman RF, Ashwood P (2014) Maternal immune activation leads to activated inflammatory macrophages in offspring. Brain Behav Immun 38:220–226. doi: 10.1016/j.bbi.2014.02.007 PubMedCentralPubMedCrossRefGoogle Scholar
  92. Oskvig DB, Elkahloun AG, Johnson KR, Phillips TM, Herkenham M (2012) Maternal immune activation by LPS selectively alters specific gene expression profiles of interneuron migration and oxidative stress in the fetus without triggering a fetal immune response. Brain Behav Immun 26(4):623–634. doi: 10.1016/j.bbi.2012.01.015 PubMedCentralPubMedCrossRefGoogle Scholar
  93. Owley T, Salt J, Guter S, Grieve A, Walton L, Ayuyao N, Leventhal BL, Cook EH Jr (2006) A prospective, open-label trial of memantine in the treatment of cognitive, behavioral, and memory dysfunction in pervasive developmental disorders. J Child Adolesc Psychopharmacol 16(5):517–524. doi: 10.1089/cap.2006.16.517 PubMedCrossRefGoogle Scholar
  94. Page LA, Daly E, Schmitz N, Simmons A, Toal F, Deeley Q, Ambery F, McAlonan GM, Murphy KC, Murphy DG (2006) In vivo 1H-magnetic resonance spectroscopy study of amygdala-hippocampal and parietal regions in autism. Am J Psychiatry 163(12):2189–2192. doi: 10.1176/appi.ajp.163.12.2189 PubMedGoogle Scholar
  95. Patterson PH (2009) Immune involvement in schizophrenia and autism: etiology, pathology and animal models. Behav Brain Res 204(2):313–321. doi: 10.1016/j.bbr.2008.12.016 PubMedCrossRefGoogle Scholar
  96. Pelphrey KA, Sasson NJ, Reznick JS, Paul G, Goldman BD, Piven J (2002) Visual scanning of faces in autism. J Autism Dev Disord 32(4):249–261PubMedCrossRefGoogle Scholar
  97. Pelphrey K, Adolphs R, Morris JP (2004) Neuroanatomical substrates of social cognition dysfunction in autism. Ment Retard Dev Disabil Res Rev 10(4):259–271. doi: 10.1002/mrdd.20040 PubMedCrossRefGoogle Scholar
  98. Peng D, Yuan X, Zhu R (2013) Memantine hydrochloride in the treatment of dementia subtypes. J Clin Neurosci 20(11):1482–1485. doi: 10.1016/j.jocn.2013.02.041 PubMedCrossRefGoogle Scholar
  99. Perlman SB, Hudac CM, Pegors T, Minshew NJ, Pelphrey KA (2011) Experimental manipulation of face-evoked activity in the fusiform gyrus of individuals with autism. Soc Neurosci 6(1):22–30. doi: 10.1080/17470911003683185 PubMedCentralPubMedCrossRefGoogle Scholar
  100. Plioplys AV (1998) Intravenous immunoglobulin treatment of children with autism. J Child Neurol 13(2):79–82PubMedCrossRefGoogle Scholar
  101. Posey DJ, Kem DL, Swiezy NB, Sweeten TL, Wiegand RE, McDougle CJ (2004) A pilot study of d-cycloserine in subjects with autistic disorder. Am J Psychiatry 161(11):2115–2117. doi: 10.1176/appi.ajp.161.11.2115 PubMedCrossRefGoogle Scholar
  102. 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(33):13501–13506. doi: 10.1073/pnas.0704391104 PubMedCentralPubMedCrossRefGoogle Scholar
  103. Robinson IC, Jones PM (1982) Oxytocin and neurophysin in plasma and CSF during suckling in the guinea-pig. Neuroendocrinology 34(1):59–63PubMedCrossRefGoogle Scholar
  104. Ros-Bernal F, Hunot S, Herrero MT, Parnadeau S, Corvol JC, Lu L, Alvarez-Fischer D, Carrillo-de Sauvage MA, Saurini F, Coussieu C, Kinugawa K, Prigent A, Hoglinger G, Hamon M, Tronche F, Hirsch EC, Vyas S (2011) Microglial glucocorticoid receptors play a pivotal role in regulating dopaminergic neurodegeneration in Parkinsonism. Proc Natl Acad Sci USA 108(16):6632–6637. doi: 10.1073/pnas.1017820108 PubMedCentralPubMedCrossRefGoogle Scholar
  105. Sala M, Braida D, Lentini D, Busnelli M, Bulgheroni E, Capurro V, Finardi A, Donzelli A, Pattini L, Rubino T, Parolaro D, Nishimori K, Parenti M, Chini B (2011) Pharmacologic rescue of impaired cognitive flexibility, social deficits, increased aggression, and seizure susceptibility in oxytocin receptor null mice: a neurobehavioral model of autism. Biol Psychiatry 69(9):875–882. doi: 10.1016/j.biopsych.2010.12.022 PubMedCrossRefGoogle Scholar
  106. Sasson NJ, Pinkham AE, Carpenter KL, Belger A (2011) The benefit of directly comparing autism and schizophrenia for revealing mechanisms of social cognitive impairment. J Neurodev Disord 3(2):87–100. doi: 10.1007/s11689-010-9068-x PubMedCentralPubMedCrossRefGoogle Scholar
  107. Schaefer GB, Mendelsohn NJ (2013) Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med 15(5):399–407. doi: 10.1038/gim.2013.32 PubMedCrossRefGoogle Scholar
  108. Schneider T, Przewlocki R (2005) Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology 30(1):80–89. doi: 10.1038/sj.npp.1300518 PubMedCrossRefGoogle Scholar
  109. Schneider CK, Melmed RD, Barstow LE, Enriquez FJ, Ranger-Moore J, Ostrem JA (2006) Oral human immunoglobulin for children with autism and gastrointestinal dysfunction: a prospective, open-label study. J Autism Dev Disord 36(8):1053–1064. doi: 10.1007/s10803-006-0141-y PubMedCrossRefGoogle Scholar
  110. Schweingruber N, Reichardt SD, Luhder F, Reichardt HM (2012) Mechanisms of glucocorticoids in the control of neuroinflammation. J Neuroendocrinol 24(1):174–182. doi: 10.1111/j.1365-2826.2011.02161.x PubMedCrossRefGoogle Scholar
  111. Seckl J, Lightman S (1988) Cerebrospinal fluid neurohypophysial peptides in benign intracranial hypertension. J Neurol Neurosurg Psychiatry 51(12):1538–1541PubMedCentralPubMedCrossRefGoogle Scholar
  112. Shahrestani S, Kemp AH, Guastella AJ (2013) The impact of a single administration of intranasal oxytocin on the recognition of basic emotions in humans: a meta-analysis. Neuropsychopharmacology 38(10):1929–1936. doi: 10.1038/npp.2013.86 PubMedCentralPubMedCrossRefGoogle Scholar
  113. Shenoy S, Arnold S, Chatila T (2000) Response to steroid therapy in autism secondary to autoimmune lymphoproliferative syndrome. J Pediatr 136(5):682–687. doi: 10.1067/mpd.2000.105355 PubMedCrossRefGoogle Scholar
  114. Shi L, Fatemi SH, Sidwell RW, Patterson PH (2003) Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J Neurosci 23(1):297–302PubMedGoogle Scholar
  115. Smith SE, Li J, Garbett K, Mirnics K, Patterson PH (2007) Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci 27(40):10695–10702. doi:10.1523/JNEUROSCI. 2178-07.2007PubMedCentralPubMedCrossRefGoogle Scholar
  116. Smith SE, Zhou YD, Zhang G, Jin Z, Stoppel DC, Anderson MP (2011) Increased gene dosage of Ube3a results in autism traits and decreased glutamate synaptic transmission in mice. Sci Transl Med 3(103):103ra97. doi: 10.1126/scitranslmed.3002627 PubMedCentralPubMedCrossRefGoogle Scholar
  117. Soto D, Altafaj X, Sindreu C, Bayes A (2014) Glutamate receptor mutations in psychiatric and neurodevelopmental disorders. Commun Integr Biol 7(1):e27887. doi: 10.4161/cib.27887 PubMedCentralPubMedCrossRefGoogle Scholar
  118. Stefanatos GA, Grover W, Geller E (1995) Case study: corticosteroid treatment of language regression in pervasive developmental disorder. J Am Acad Child Adolesc Psychiatry 34(8):1107–1111. doi: 10.1097/00004583-199508000-00022 PubMedCrossRefGoogle Scholar
  119. Sterling L, Dawson G, Webb S, Murias M, Munson J, Panagiotides H, Aylward E (2008) The role of face familiarity in eye tracking of faces by individuals with autism spectrum disorders. J Autism Dev Disord 38(9):1666–1675. doi: 10.1007/s10803-008-0550-1 PubMedCentralPubMedCrossRefGoogle Scholar
  120. Stigler KA, Sweeten TL, Posey DJ, McDougle CJ (2009) Autism and immune factors: a comprehensive review. Res Autism Spectrum Disord 3(4):840–860. doi:10.1016/j.rasd. 2009.01-007CrossRefGoogle Scholar
  121. Supekar K, Uddin LQ, Khouzam A, Phillips J, Gaillard WD, Kenworthy LE, Yerys BE, Vaidya CJ, Menon V (2013) Brain hyperconnectivity in children with autism and its links to social deficits. Cell Rep 5(3):738–747. doi: 10.1016/j.celrep.2013.10.001 PubMedCentralPubMedCrossRefGoogle Scholar
  122. Suzuki K, Sugihara G, Ouchi Y, Nakamura K, Futatsubashi M, Takebayashi K, Yoshihara Y, Omata K, Matsumoto K, Tsuchiya K, Iwata Y, Tsujii M, Sugiyama T, Mori N (2013) Microglial activation in young adults with autism spectrum disorders. JAMA Psychiatry 70(1):49–58. doi: 10.1001/jamapsychiatry.2013.272 PubMedCrossRefGoogle Scholar
  123. Takayanagi Y, Yoshida M, Bielsky IF, Ross HE, Kawamata M, Onaka T, Yanagisawa T, Kimura T, Matzuk MM, Young LJ, Nishimori K (2005) Pervasive social deficits, but normal parturition, in oxytocin receptor-deficient mice. Proc Natl Acad Sci USA 102(44):16096–16101. doi: 10.1073/pnas.0505312102 PubMedCentralPubMedCrossRefGoogle Scholar
  124. Teng BL, Nonneman RJ, Agster KL, Nikolova VD, Davis TT, Riddick NV, Baker LK, Pedersen CA, Jarstfer MB, Moy SS (2013) Prosocial effects of oxytocin in two mouse models of autism spectrum disorders. Neuropharmacology 72:187–196. doi: 10.1016/j.neuropharm.2013.04.038 PubMedCentralPubMedCrossRefGoogle Scholar
  125. Trajkovski V, Ajdinski L, Spiroski M (2004) Plasma concentration of immunoglobulin classes and subclasses in children with autism in the Republic of Macedonia: retrospective study. Croat Med J 45:746–749PubMedGoogle Scholar
  126. Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, Hansen KB, Yuan H, Myers SJ, Dingledine R (2010) Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev 62(3):405–496. doi: 10.1124/pr.109.002451 PubMedCentralPubMedCrossRefGoogle Scholar
  127. Uljarevic M, Hamilton A (2013) Recognition of emotions in autism: a formal meta-analysis. J Autism Dev Disord 43(7):1517–1526. doi: 10.1007/s10803-012-1695-5 PubMedCrossRefGoogle Scholar
  128. Veening JG, Olivier B (2013) Intranasal administration of oxytocin: behavioral and clinical effects, a review. Neurosci Biobehav Rev 37(8):1445–1465. doi: 10.1016/j.neubiorev.2013.04.012 PubMedCrossRefGoogle Scholar
  129. von dem Hagen EA, Stoyanova RS, Baron-Cohen S, Calder AJ (2013) Reduced functional connectivity within and between ‘social’ resting state networks in autism spectrum conditions. Soc Cogn Affect Neurosci 8(6):694–701. doi: 10.1093/scan/nss053 CrossRefGoogle Scholar
  130. Watanabe T, Abe O, Kuwabara H, Yahata N, Takano Y, Iwashiro N, Natsubori T, Aoki Y, Takao H, Kawakubo Y, Kamio Y, Kato N, Miyashita Y, Kasai K, Yamasue H (2013) Mitigation of sociocommunicational deficits of autism through oxytocin-induced recovery of medial prefrontal activity: a randomized trial. JAMA Psychiatry 71(2):166–175. doi: 10.1001/jamapsychiatry.2013.3181 CrossRefGoogle Scholar
  131. Weigelt S, Koldewyn K, Kanwisher N (2012) Face identity recognition in autism spectrum disorders: a review of behavioral studies. Neurosci Biobehav Rev 36(3):1060–1084PubMedCrossRefGoogle Scholar
  132. Weng SJ, Carrasco M, Swartz JR, Wiggins JL, Kurapati N, Liberzon I, Risi S, Lord C, Monk CS (2011) Neural activation to emotional faces in adolescents with autism spectrum disorders. J Child Psychol Psychiatry 52(3):296–305. doi: 10.1111/j.1469-7610.2010.02317.x PubMedCentralPubMedCrossRefGoogle Scholar
  133. Winslow JT, Insel TR (2002) The social deficits of the oxytocin knockout mouse. Neuropeptides 36(2–3):221–229PubMedCrossRefGoogle Scholar
  134. Winslow JT, Hearn EF, Ferguson J, Young LJ, Matzuk MM, Insel TR (2000) Infant vocalization, adult aggression, and fear behavior of an oxytocin null mutant mouse. Horm Behav 37(2):145–155. doi: 10.1006/hbeh.1999.1566 PubMedCrossRefGoogle Scholar
  135. Won H, Lee HR, Gee HY, Mah W, Kim JI, Lee J, Ha S, Chung C, Jung ES, Cho YS, Park SG, Lee JS, Lee K, Kim D, Bae YC, Kaang BK, Lee MG, Kim E (2012) Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function. Nature 486(7402):261–265. doi: 10.1038/nature11208 PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Arshya Vahabzadeh
    • 1
    • 2
    • 3
  • Samantha M. Landino
    • 4
  • Beate C. Finger
    • 3
    • 4
  • William A. CarlezonJr.
    • 3
    • 4
  • Christopher J. McDougle
    • 1
    • 3
    • 5
    Email author
  1. 1.Massachusetts General HospitalBostonUSA
  2. 2.McLean HospitalBelmontUSA
  3. 3.Harvard Medical SchoolBostonUSA
  4. 4.Behavioral Genetics LaboratoryMcLean HospitalBelmontUSA
  5. 5.Lurie Center for AutismLexingtonUSA

Personalised recommendations