Advertisement

Oxytocin and Animal Models for Autism Spectrum Disorder

  • Shlomo Wagner
  • Hala Harony-Nicolas
Chapter
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 35)

Abstract

Autism spectrum disorder (ASD) is a group of complex neurodevelopmental conditions characterized by deficits in social communication and by repetitive and stereotypic patterns of behaviors, with no pharmacological treatments available to treat these core symptoms. Oxytocin is a neuropeptide that powerfully regulates mammalian social behavior and has been shown to exert pro-social effects when administered intranasally to healthy human subjects. In the last decade, there has been a significant interest in using oxytocin to treat social behavior deficits in ASD. However, little attention has been paid to whether the oxytocin system is perturbed in subgroups of individuals with ASD and whether these individuals are likely to benefit more from an oxytocin treatment. This oversight may in part be due to the enormous heterogeneity of ASD and the lack of methods to carefully probe the OXT system in human subjects. Animal models for ASD are valuable tools to clarify the implication of the oxytocin system in ASD and can help determine whether perturbation in this system should be considered in future clinical studies as stratifying biomarkers to inform targeted treatments in subgroups of individuals with ASD. In this chapter, we review the literature on genetic- and environmental-based animal models for ASD, in which perturbations in the oxytocin system and/or the effect of oxytocin administration on the ASD-associated phenotype have been investigated.

Keywords

ASD animal models Autism spectrum disorder (ASD) Oxytocin 

References

  1. American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, WashingtonGoogle Scholar
  2. Angulo MA, Butler MG, Cataletto ME (2015) Prader-Willi syndrome: a review of clinical, genetic, and endocrine findings. J Endocrinol Investig 38(12):1249–1263. doi: 10.1007/s40618-015-0312-9CrossRefGoogle Scholar
  3. Ascano M Jr, Mukherjee N, Bandaru P, Miller JB, Nusbaum JD, Corcoran DL, Langlois C, Munschauer M, Dewell S, Hafner M, Williams Z, Ohler U, Tuschl T (2012) FMRP targets distinct mRNA sequence elements to regulate protein expression. Nature 492(7429):382–386. doi: 10.1038/nature11737CrossRefPubMedPubMedCentralGoogle Scholar
  4. Ben-Ari Y, Tseeb V, Raggozzino D, Khazipov R, Gaiarsa JL (1994) Gamma-aminobutyric acid (GABA): a fast excitatory transmitter which may regulate the development of hippocampal neurones in early postnatal life. Prog Brain Res 102:261–273. doi: 10.1016/S0079-6123(08)60545-2CrossRefPubMedGoogle Scholar
  5. Bennett JA, Germani T, Haqq AM, Zwaigenbaum L (2015) Autism spectrum disorder in Prader-Willi syndrome: a systematic review. Am J Med Genet A 167A(12):2936–2944. doi: 10.1002/ajmg.a.37286CrossRefPubMedGoogle Scholar
  6. Bervini S, Herzog H (2013) Mouse models of Prader-Willi syndrome: a systematic review. Front Neuroendocrinol 34(2):107–119. doi: 10.1016/j.yfrne.2013.01.002CrossRefPubMedGoogle Scholar
  7. Betancur C, Sakurai T, Buxbaum JD (2009) The emerging role of synaptic cell-adhesion pathways in the pathogenesis of autism spectrum disorders. Trends Neurosci 32(7):402–412. doi: 10.1016/j.tins.2009.04.003CrossRefPubMedGoogle Scholar
  8. Bhattacharya A, Kaphzan H, Alvarez-Dieppa AC, Murphy JP, Pierre P, Klann E (2012) Genetic removal of p70 S6 kinase 1 corrects molecular, synaptic, and behavioral phenotypes in fragile X syndrome mice. Neuron 76(2):325–337. doi: 10.1016/j.neuron.2012.07.022CrossRefPubMedPubMedCentralGoogle Scholar
  9. Bittel DC, Kibiryeva N, Dasouki M, Knoll JH, Butler MG (2006) A 9-year-old male with a duplication of chromosome 3p25.3p26.2: clinical report and gene expression analysis. Am J Med Genet A 140(6):573–579CrossRefPubMedPubMedCentralGoogle Scholar
  10. Blatt GJ (2005) GABAergic cerebellar system in autism: a neuropathological and developmental perspective. Int Rev Neurobiol 71:167–178CrossRefPubMedGoogle Scholar
  11. Bromley RL, Mawer G, Clayton-Smith J, Baker GA, Liverpool and Manchester Neurodevelopment Group (2008) Autism spectrum disorders following in utero exposure to antiepileptic drugs. Neurology 71(23):1923–1924. doi: 10.1212/01.wnl.0000339399.64213.1aCrossRefPubMedGoogle Scholar
  12. Brunner D, Kabitzke P, He D, Cox K, Thiede L, Hanania T, Sabath E, Alexandrov V, Saxe M, Peles E, Mills A, Spooren W, Ghosh A, Feliciano P, Benedetti M, Luo Clayton A, Biemans B (2015) Comprehensive analysis of the 16p11.2 deletion and null Cntnap2 mouse models of autism spectrum disorder. PLoS One 10(8):e0134572. doi: 10.1371/journal.pone.0134572CrossRefPubMedPubMedCentralGoogle Scholar
  13. Buxbaum JD, Betancur C, Bozdagi O, Dorr NP, Elder GA, Hof PR (2012) Optimizing the phenotyping of rodent ASD models: enrichment analysis of mouse and human neurobiological phenotypes associated with high-risk autism genes identifies morphological, electrophysiological, neurological, and behavioral features. Mol Autism 3(1):1. doi: 10.1186/2040-2392-3-1CrossRefPubMedPubMedCentralGoogle Scholar
  14. Cherubini E, Gaiarsa JL, Ben-Ari Y (1991) GABA: an excitatory transmitter in early postnatal life. Trends Neurosci 14(12):515–519CrossRefPubMedGoogle Scholar
  15. Christensen J, Gronborg TK, Sorensen MJ, Schendel D, Parner ET, Pedersen LH, Vestergaard M (2013) Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA 309(16):1696–1703. doi: 10.1001/jama.2013.2270CrossRefPubMedPubMedCentralGoogle Scholar
  16. Cook EH Jr, Scherer SW (2008) Copy-number variations associated with neuropsychiatric conditions. Nature 455(7215):919–923. doi: 10.1038/nature07458CrossRefPubMedGoogle Scholar
  17. Crawley JN, Chen T, Puri A, Washburn R, Sullivan TL, Hill JM, Young NB, Nadler JJ, Moy SS, Young LJ, Caldwell HK, Young WS (2007) Social approach behaviors in oxytocin knockout mice: comparison of two independent lines tested in different laboratory environments. Neuropeptides 41(3):145–163. doi: 10.1016/j.npep.2007.02.002CrossRefPubMedGoogle Scholar
  18. Darnell JC, Van Driesche SJ, Zhang C, Hung KY, Mele A, Fraser CE, Stone EF, Chen C, Fak JJ, Chi SW, Licatalosi DD, Richter JD, Darnell RB (2011) FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146(2):247–261. doi: 10.1016/j.cell.2011.06.013CrossRefPubMedPubMedCentralGoogle Scholar
  19. De Rubeis S, Buxbaum JD (2015) Recent advances in the genetics of autism spectrum disorder. Curr Neurol Neurosci Rep 15(6):36. doi: 10.1007/s11910-015-0553-1CrossRefPubMedGoogle Scholar
  20. De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, Kou Y, Liu L, Fromer M, Walker S, Singh T, Klei L, Kosmicki J, Shih-Chen F, Aleksic B, Biscaldi M, Bolton PF, Brownfeld JM, Cai J, Campbell NG, Carracedo A, Chahrour MH, Chiocchetti AG, Coon H, Crawford EL, Curran SR, Dawson G, Duketis E, Fernandez BA, Gallagher L, Geller E, Guter SJ, Hill RS, Ionita-Laza J, Jimenz Gonzalez P, Kilpinen H, Klauck SM, Kolevzon A, Lee I, Lei I, Lei J, Lehtimaki T, Lin CF, Ma’ayan A, Marshall CR, McInnes AL, Neale B, Owen MJ, Ozaki N, Parellada M, Parr JR, Purcell S, Puura K, Rajagopalan D, Rehnstrom K, Reichenberg A, Sabo A, Sachse M, Sanders SJ, Schafer C, Schulte-Ruther M, Skuse D, Stevens C, Szatmari P, Tammimies K, Valladares O, Voran A, Li-San W, Weiss LA, Willsey AJ, Yu TW, Yuen RK, Study DDD, Homozygosity Mapping Collaborative for Autism, Consortium UK, Cook EH, Freitag CM, Gill M, Hultman CM, Lehner T, Palotie A, Schellenberg GD, Sklar P, State MW, Sutcliffe JS, Walsh CA, Scherer SW, Zwick ME, Barett JC, Cutler DJ, Roeder K, Devlin B, Daly MJ, Buxbaum JD (2014) Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515(7526):209–215. doi: 10.1038/nature13772CrossRefPubMedPubMedCentralGoogle Scholar
  21. DeLorey TM, Handforth A, Anagnostaras SG, Homanics GE, Minassian BA, Asatourian A, Fanselow MS, Delgado-Escueta A, Ellison GD, Olsen RW (1998) Mice lacking the beta3 subunit of the GABAA receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome. J Neurosci 18(20):8505–8514CrossRefPubMedGoogle Scholar
  22. DeLorey TM, Sahbaie P, Hashemi E, Homanics GE, Clark JD (2008) Gabrb3 gene deficient mice exhibit impaired social and exploratory behaviors, deficits in non-selective attention and hypoplasia of cerebellar vermal lobules: a potential model of autism spectrum disorder. Behav Brain Res 187(2):207–220. doi: 10.1016/j.bbr.2007.09.009CrossRefPubMedGoogle Scholar
  23. den Broeder MJ, van der Linde H, Brouwer JR, Oostra BA, Willemsen R, Ketting RF (2009) Generation and characterization of FMR1 knockout zebrafish. PLoS One 4(11):e7910. doi: 10.1371/journal.pone.0007910CrossRefGoogle Scholar
  24. Dolen G, Osterweil E, Rao BS, Smith GB, Auerbach BD, Chattarji S, Bear MF (2007) Correction of fragile X syndrome in mice. Neuron 56(6):955–962. doi: 10.1016/j.neuron.2007.12.001CrossRefPubMedPubMedCentralGoogle Scholar
  25. Dombret C, Nguyen T, Schakman O, Michaud JL, Hardin-Pouzet H, Bertrand MJ, De Backer O (2012) Loss of Maged1 results in obesity, deficits of social interactions, impaired sexual behavior and severe alteration of mature oxytocin production in the hypothalamus. Hum Mol Genet 21(21):4703–4717. doi: 10.1093/hmg/dds310CrossRefPubMedGoogle Scholar
  26. Duarte ST, Armstrong J, Roche A, Ortez C, Perez A, O’Callaghan MD, Pereira A, Sanmarti F, Ormazabal A, Artuch R, Pineda M, Garcia-Cazorla A (2013) Abnormal expression of cerebrospinal fluid cation chloride cotransporters in patients with Rett syndrome. PLoS One 8(7):e68851. doi: 10.1371/journal.pone.0068851CrossRefPubMedPubMedCentralGoogle Scholar
  27. Dufour-Rainfray D, Vourc'h P, Le Guisquet AM, Garreau L, Ternant D, Bodard S, Jaumain E, Gulhan Z, Belzung C, Andres CR, Chalon S, Guilloteau D (2010) Behavior and serotonergic disorders in rats exposed prenatally to valproate: a model for autism. Neurosci Lett 470(1):55–59. doi: 10.1016/j.neulet.2009.12.054CrossRefPubMedGoogle Scholar
  28. Eftekhari S, Shahrokhi A, Tsintsadze V, Nardou R, Brouchoud C, Conesa M, Burnashev N, Ferrari DC, Ben-Ari Y (2014) Response to comment on “oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring”. Science 346(6206):176. doi: 10.1126/science.1256009CrossRefPubMedGoogle Scholar
  29. Elia J, Gai X, Xie HM, Perin JC, Geiger E, Glessner JT, D’Arcy M, deBerardinis R, Frackelton E, Kim C, Lantieri F, Muganga BM, Wang L, Takeda T, Rappaport EF, Grant SF, Berrettini W, Devoto M, Shaikh TH, Hakonarson H, White PS (2010) Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes. Mol Psychiatry 15(6):637–646. doi: 10.1038/mp.2009.57CrossRefPubMedGoogle Scholar
  30. Ergaz Z, Weinstein-Fudim L, Ornoy A (2016) Genetic and non-genetic animal models for autism spectrum disorders (ASD). Reprod Toxicol 64:116–140. doi: 10.1016/j.reprotox.2016.04.024CrossRefPubMedGoogle Scholar
  31. Farrant M, Kaila K (2007) The cellular, molecular and ionic basis of GABA(A) receptor signalling. Prog Brain Res 160:59–87. doi: 10.1016/S0079-6123(06)60005-8CrossRefPubMedGoogle Scholar
  32. 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: 10.1038/77040CrossRefPubMedGoogle Scholar
  33. Fujiwara T, Sanada M, Kofuji T, Akagawa K (2016) Unusual social behavior in HPC-1/syntaxin1A knockout mice is caused by disruption of the oxytocinergic neural system. J Neurochem 138(1):117–123. doi: 10.1111/jnc.13634CrossRefPubMedGoogle Scholar
  34. Garber KB, Visootsak J, Warren ST (2008) Fragile X syndrome. Eur J Hum Genet 16(6):666–672. doi: 10.1038/ejhg.2008.61CrossRefPubMedPubMedCentralGoogle Scholar
  35. Gauthier J, Champagne N, Lafreniere RG, Xiong L, Spiegelman D, Brustein E, Lapointe M, Peng H, Cote M, Noreau A, Hamdan FF, Addington AM, Rapoport JL, Delisi LE, Krebs MO, Joober R, Fathalli F, Mouaffak F, Haghighi AP, Neri C, Dube MP, Samuels ME, Marineau C, Stone EA, Awadalla P, Barker PA, Carbonetto S, Drapeau P, Rouleau GA (2010) De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia. Proc Natl Acad Sci U S A 107(17):7863–7868. doi: 10.1073/pnas.0906232107CrossRefPubMedPubMedCentralGoogle Scholar
  36. Gigliucci V, Leonzino M, Busnelli M, Luchetti A, Palladino VS, D’Amato FR, Chini B (2014) Region specific up-regulation of oxytocin receptors in the opioid oprm1 (−/−) mouse model of autism. Front Pediatr 2:91. doi: 10.3389/fped.2014.00091CrossRefPubMedPubMedCentralGoogle Scholar
  37. Gkogkas CG, Khoutorsky A, Cao R, Jafarnejad SM, Prager-Khoutorsky M, Giannakas N, Kaminari A, Fragkouli A, Nader K, Price TJ, Konicek BW, Graff JR, Tzinia AK, Lacaille JC, Sonenberg N (2014) Pharmacogenetic inhibition of eIF4E-dependent Mmp9 mRNA translation reverses fragile X syndrome-like phenotypes. Cell Rep 9(5):1742–1755. doi: 10.1016/j.celrep.2014.10.064CrossRefPubMedPubMedCentralGoogle Scholar
  38. Gocel J, Larson J (2012) Synaptic NMDA receptor-mediated currents in anterior piriform cortex are reduced in the adult fragile X mouse. Neuroscience 221:170–181. doi: 10.1016/j.neuroscience.2012.06.052CrossRefPubMedPubMedCentralGoogle Scholar
  39. Gong X, Jiang YW, Zhang X, An Y, Zhang J, Wu Y, Wang J, Sun Y, Liu Y, Gao X, Shen Y, Wu X, Qiu Z, Jin L, Wu BL, Wang H (2012) High proportion of 22q13 deletions and SHANK3 mutations in Chinese patients with intellectual disability. PLoS One 7(4):e34739. doi: 10.1371/journal.pone.0034739CrossRefPubMedPubMedCentralGoogle Scholar
  40. Gottlicher M, Minucci S, Zhu P, Kramer OH, Schimpf A, Giavara S, Sleeman JP, Lo Coco F, Nervi C, Pelicci PG, Heinzel T (2001) Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 20(24):6969–6978. doi: 10.1093/emboj/20.24.6969CrossRefPubMedPubMedCentralGoogle Scholar
  41. Green JJ, Hollander E (2010) Autism and oxytocin: new developments in translational approaches to therapeutics. Neurotherapeutics 7(3):250–257. doi: 10.1016/j.nurt.2010.05.006CrossRefPubMedPubMedCentralGoogle Scholar
  42. Greer PL, Hanayama R, Bloodgood BL, Mardinly AR, Lipton DM, Flavell SW, Kim TK, Griffith EC, Waldon Z, Maehr R, Ploegh HL, Chowdhury S, Worley PF, Steen J, Greenberg ME (2010) The Angelman syndrome protein Ube3A regulates synapse development by ubiquitinating arc. Cell 140(5):704–716. doi: 10.1016/j.cell.2010.01.026CrossRefPubMedPubMedCentralGoogle Scholar
  43. Gregory SG, Connelly JJ, Towers AJ, Johnson J, Biscocho D, Markunas CA, Lintas C, Abramson RK, Wright HH, Ellis P, Langford CF, Worley G, Delong GR, Murphy SK, Cuccaro ML, Persico A, Pericak-Vance MA (2009) Genomic and epigenetic evidence for oxytocin receptor deficiency in autism. BMC Med 7:62. doi: 10.1186/1741-7015-7-62CrossRefPubMedPubMedCentralGoogle Scholar
  44. Guastella AJ, Hickie IB (2016) Oxytocin treatment, circuitry and autism: a critical review of the literature placing oxytocin into the autism context. Biol Psychiatry 79(3):234–242. doi: 10.1016/j.biopsych.2015.06.028CrossRefPubMedGoogle Scholar
  45. Hadjikhani N, Zurcher NR, Rogier O, Ruest T, Hippolyte L, Ben-Ari Y, Lemonnier E (2015) Improving emotional face perception in autism with diuretic bumetanide: a proof-of-concept behavioral and functional brain imaging pilot study. Autism 19(2):149–157. doi: 10.1177/1362361313514141CrossRefPubMedGoogle Scholar
  46. Hamdan FF, Gauthier J, Araki Y, Lin DT, Yoshizawa Y, Higashi K, Park AR, Spiegelman D, Dobrzeniecka S, Piton A, Tomitori H, Daoud H, Massicotte C, Henrion E, Diallo O, Group SD, Shekarabi M, Marineau C, Shevell M, Maranda B, Mitchell G, Nadeau A, D’Anjou G, Vanasse M, Srour M, Lafreniere RG, Drapeau P, Lacaille JC, Kim E, Lee JR, Igarashi K, Huganir RL, Rouleau GA, Michaud JL (2011) Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Am J Hum Genet 88(3):306–316. doi: 10.1016/j.ajhg.2011.02.001CrossRefPubMedPubMedCentralGoogle Scholar
  47. Hamilton SM, Green JR, Veeraragavan S, Yuva L, McCoy A, Wu Y, Warren J, Little L, Ji D, Cui X, Weinstein E, Paylor R (2014) Fmr1 and Nlgn3 knockout rats: novel tools for investigating autism spectrum disorders. Behav Neurosci 128(2):103–109. doi: 10.1037/a0035988CrossRefPubMedGoogle Scholar
  48. Hammock EA, Young LJ (2006) Oxytocin, vasopressin and pair bonding: implications for autism. Philos Trans R Soc Lond Ser B Biol Sci 361(1476):2187–2198CrossRefGoogle Scholar
  49. Harony H, Wagner S (2010) The contribution of oxytocin and vasopressin to mammalian social behavior: potential role in autism spectrum disorder. Neurosignals 18(2):82–97. doi: 10.1159/000321035CrossRefPubMedGoogle Scholar
  50. Harony-Nicolas H, Kay M, Hoffmann JD, Klein ME, Bozdagi-Gunal O, Riad M, Daskalakis NP, Sonar S, Castillo PE, Hof PR, Shapiro ML, Baxter MG, Wagner S, Buxbaum JD (2017) Oxytocin improves behavioral and electrophysiological deficits in a novel Shank3-deficient rat. Elife 6:e18904. doi: 10.7554/eLife.18904CrossRefPubMedPubMedCentralGoogle Scholar
  51. He Q, Nomura T, Xu J, Contractor A (2014) The developmental switch in GABA polarity is delayed in fragile X mice. J Neurosci 34(2):446–450. doi: 10.1523/Jneurosci.4447-13.2014CrossRefPubMedGoogle Scholar
  52. Heinrichs M, von Dawans B, Domes G (2009) Oxytocin, vasopressin, and human social behavior. Front Neuroendocrinol 30(4):548–557. doi: 10.1016/j.yfrne.2009.05.005CrossRefPubMedGoogle Scholar
  53. Higashida H, Lopatina O, Yoshihara T, Pichugina YA, Soumarokov AA, Munesue T, Minabe Y, Kikuchi M, Ono Y, Korshunova N, Salmina AB (2010) Oxytocin signal and social behaviour: comparison among adult and infant oxytocin, oxytocin receptor and CD38 gene knockout mice. J Neuroendocrinol 22(5):373–379. doi: 10.1111/j.1365-2826.2010.01976.xCrossRefPubMedGoogle Scholar
  54. 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.2011.12.011CrossRefPubMedGoogle Scholar
  55. Homanics GE, DeLorey TM, Firestone LL, Quinlan JJ, Handforth A, Harrison NL, Krasowski MD, Rick CE, Korpi ER, Makela R, Brilliant MH, Hagiwara N, Ferguson C, Snyder K, Olsen RW (1997) Mice devoid of gamma-aminobutyrate type A receptor beta3 subunit have epilepsy, cleft palate, and hypersensitive behavior. Proc Natl Acad Sci U S A 94(8):4143–4148CrossRefPubMedPubMedCentralGoogle Scholar
  56. Huber KM, Roder JC, Bear MF (2001) Chemical induction of mGluR5- and protein synthesis-dependent long-term depression in hippocampal area CA1. J Neurophysiol 86(1):321–325CrossRefPubMedGoogle Scholar
  57. Ingram JL, Peckham SM, Tisdale B, Rodier PM (2000) Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism. Neurotoxicol Teratol 22(3):319–324CrossRefPubMedGoogle Scholar
  58. Insel TR, O'Brien DJ, Leckman JF (1999) Oxytocin, vasopressin, and autism: is there a connection? Biol Psychiatry 45(2):145–157CrossRefPubMedGoogle Scholar
  59. Iossifov I, O'Roak BJ, Sanders SJ, Ronemus M, Krumm N, Levy D, Stessman HA, Witherspoon KT, Vives L, Patterson KE, Smith JD, Paeper B, Nickerson DA, Dea J, Dong S, Gonzalez LE, Mandell JD, Mane SM, Murtha MT, Sullivan CA, Walker MF, Waqar Z, Wei L, Willsey AJ, Yamrom B, Lee YH, Grabowska E, Dalkic E, Wang Z, Marks S, Andrews P, Leotta A, Kendall J, Hakker I, Rosenbaum J, Ma B, Rodgers L, Troge J, Narzisi G, Yoon S, Schatz MC, Ye K, McCombie WR, Shendure J, Eichler EE, State MW, Wigler M (2014) The contribution of de novo coding mutations to autism spectrum disorder. Nature 515(7526):216–221. doi: 10.1038/nature13908CrossRefPubMedPubMedCentralGoogle Scholar
  60. Jana NR (2012) Understanding the pathogenesis of Angelman syndrome through animal models. Neural Plast 2012:710943. doi: 10.1155/2012/710943CrossRefPubMedPubMedCentralGoogle Scholar
  61. 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/nature05526CrossRefPubMedGoogle Scholar
  62. Kataoka S, Takuma K, Hara Y, Maeda Y, Ago Y, Matsuda T (2013) Autism-like behaviours with transient histone hyperacetylation in mice treated prenatally with valproic acid. Int J Neuropsychopharmacol 16(1):91–103. doi: 10.1017/S1461145711001714CrossRefPubMedGoogle Scholar
  63. Kazdoba TM, Leach PT, Silverman JL, Crawley JN (2014) Modeling fragile X syndrome in the Fmr1 knockout mouse. Intractable Rare Dis Res 3(4):118–133. doi: 10.5582/irdr.2014.01024CrossRefPubMedPubMedCentralGoogle Scholar
  64. Kim KC, Kim P, Go HS, Choi CS, Yang SI, Cheong JH, Shin CY, Ko KH (2011) The critical period of valproate exposure to induce autistic symptoms in Sprague-Dawley rats. Toxicol Lett 201(2):137–142. doi: 10.1016/j.toxlet.2010.12.018CrossRefPubMedGoogle Scholar
  65. La Fata G, Gartner A, Dominguez-Iturza N, Dresselaers T, Dawitz J, Poorthuis RB, Averna M, Himmelreich U, Meredith RM, Achsel T, Dotti CG, Bagni C (2014) FMRP regulates multipolar to bipolar transition affecting neuronal migration and cortical circuitry. Nat Neurosci 17(12):1693–1700. doi: 10.1038/nn.3870CrossRefPubMedGoogle Scholar
  66. Lee HJ, Caldwell HK, Macbeth AH, Tolu SG, Young WS 3rd (2008) A conditional knockout mouse line of the oxytocin receptor. Endocrinology 149(7):3256–3263CrossRefPubMedPubMedCentralGoogle Scholar
  67. Lee SY, Lee AR, Hwangbo R, Han J, Hong M, Bahn GH (2015) Is oxytocin application for autism spectrum disorder evidence-based? Exp Neurobiol 24(4):312–324. doi: 10.5607/en.2015.24.4.312CrossRefPubMedPubMedCentralGoogle Scholar
  68. Lemonnier E, Ben-Ari Y (2010) The diuretic bumetanide decreases autistic behaviour in five infants treated during 3 months with no side effects. Acta Paediatr 99(12):1885–1888. doi: 10.1111/j.1651-2227.2010.01933.xCrossRefPubMedGoogle Scholar
  69. Lemonnier E, Degrez C, Phelep M, Tyzio R, Josse F, Grandgeorge M, Hadjikhani N, Ben-Ari Y (2012) A randomised controlled trial of bumetanide in the treatment of autism in children. Transl Psychiatry 2:e202. doi: 10.1038/tp.2012.124CrossRefPubMedPubMedCentralGoogle Scholar
  70. Lemonnier E, Robin G, Degrez C, Tyzio R, Grandgeorge M, Ben-Ari Y (2013) Treating fragile X syndrome with the diuretic bumetanide: a case report. Acta Paediatr 102(6):e288–e290. doi: 10.1111/apa.12235CrossRefPubMedGoogle Scholar
  71. Leonzino M, Busnelli M, Antonucci F, Verderio C, Mazzanti M, Chini B (2016) The timing of the excitatory-to-inhibitory GABA switch is regulated by the oxytocin receptor via KCC2. Cell Rep 15(1):96–103. doi: 10.1016/j.celrep.2016.03.013CrossRefPubMedPubMedCentralGoogle Scholar
  72. Liu B, Li L, Chen J, Wang Z, Li Z, Wan Q (2013) Regulation of GABAA receptors by fragile X mental retardation protein. Int J Physiol Pathophysiol Pharmacol 5(3):169–176PubMedPubMedCentralGoogle Scholar
  73. 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.2012.08.011CrossRefPubMedPubMedCentralGoogle Scholar
  74. Margolis SS, Sell GL, Zbinden MA, Bird LM (2015) Angelman syndrome. Neurotherapeutics 12(3):641–650. doi: 10.1007/s13311-015-0361-yCrossRefPubMedPubMedCentralGoogle Scholar
  75. McKinney BC, Grossman AW, Elisseou NM, Greenough WT (2005) Dendritic spine abnormalities in the occipital cortex of C57BL/6 Fmr1 knockout mice. Am J Med Genet B Neuropsychiatr Genet 136B(1):98–102. doi: 10.1002/ajmg.b.30183CrossRefPubMedGoogle Scholar
  76. Meador K, Reynolds MW, Crean S, Fahrbach K, Probst C (2008) Pregnancy outcomes in women with epilepsy: a systematic review and meta-analysis of published pregnancy registries and cohorts. Epilepsy Res 81(1):1–13. doi: 10.1016/j.eplepsyres.2008.04.022CrossRefPubMedPubMedCentralGoogle Scholar
  77. Mefford HC, Muhle H, Ostertag P, von Spiczak S, Buysse K, Baker C, Franke A, Malafosse A, Genton P, Thomas P, Gurnett CA, Schreiber S, Bassuk AG, Guipponi M, Stephani U, Helbig I, Eichler EE (2010) Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies. PLoS Genet 6(5):e1000962. doi: 10.1371/journal.pgen.1000962CrossRefPubMedPubMedCentralGoogle Scholar
  78. Meziane H, Schaller F, Bauer S, Villard C, Matarazzo V, Riet F, Guillon G, Lafitte D, Desarmenien MG, Tauber M, Muscatelli F (2015) An early postnatal oxytocin treatment prevents social and learning deficits in adult mice deficient for Magel2, a gene involved in Prader-Willi syndrome and autism. Biol Psychiatry 78(2):85–94. doi: 10.1016/j.biopsych.2014.11.010CrossRefPubMedGoogle Scholar
  79. Modahl C, Fein D, Waterhouse L, Newton N (1992) Does oxytocin deficiency mediate social deficits in autism. J Autism Dev Disord 22(3):449–451. doi: 10.1007/Bf01048246CrossRefPubMedGoogle Scholar
  80. Muscatelli F, Abrous DN, Massacrier A, Boccaccio I, Le Moal M, Cau P, Cremer H (2000) Disruption of the mouse Necdin gene results in hypothalamic and behavioral alterations reminiscent of the human Prader-Willi syndrome. Hum Mol Genet 9(20):3101–3110CrossRefPubMedGoogle Scholar
  81. Nakatani J, Tamada K, Hatanaka F, Ise S, Ohta H, Inoue K, Tomonaga S, Watanabe Y, Chung YJ, Banerjee R, Iwamoto K, Kato T, Okazawa M, Yamauchi K, Tanda K, Takao K, Miyakawa T, Bradley A, Takumi T (2009) Abnormal behavior in a chromosome-engineered mouse model for human 15q11-13 duplication seen in autism. Cell 137(7):1235–1246. doi: 10.1016/j.cell.2009.04.024CrossRefPubMedPubMedCentralGoogle Scholar
  82. Olza Fernandez I, Marin Gabriel MA, Lopez Sanchez F, Malalana Martinez AM (2011) Oxytocin and autism: a hypothesis to research. Can perinatal oxitocinergic manipulation facilitate autism? Rev Psiquiatr Salud Ment 4(1):38–41. doi: 10.1016/j.rpsm.2010.10.004CrossRefPubMedGoogle Scholar
  83. Ornoy A (2009) Valproic acid in pregnancy: how much are we endangering the embryo and fetus? Reprod Toxicol 28(1):1–10. doi: 10.1016/j.reprotox.2009.02.014CrossRefPubMedGoogle Scholar
  84. Payne JA, Rivera C, Voipio J, Kaila K (2003) Cation-chloride co-transporters in neuronal communication, development and trauma. Trends Neurosci 26(4):199–206. doi: 10.1016/S0166-2236(03)00068-7CrossRefPubMedGoogle Scholar
  85. Pedersen CA, Vadlamudi SV, Boccia ML, Amico JA (2006) Maternal behavior deficits in nulliparous oxytocin knockout mice. Genes Brain Behav 5(3):274–281. doi: 10.1111/j.1601-183X.2005.00162.xCrossRefPubMedGoogle Scholar
  86. Penagarikano O, Lazaro MT, Lu XH, Gordon A, Dong H, Lam HA, Peles E, Maidment NT, Murphy NP, Yang XW, Golshani P, Geschwind DH (2015) Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism. Sci Transl Med 7(271):271ra278. doi: 10.1126/scitranslmed.3010257CrossRefGoogle Scholar
  87. Pobbe RL, Pearson BL, Defensor EB, Bolivar VJ, Young WS 3rd, Lee HJ, Blanchard DC, Blanchard RJ (2012) Oxytocin receptor knockout mice display deficits in the expression of autism-related behaviors. Horm Behav 61(3):436–444. doi: 10.1016/j.yhbeh.2011.10.010CrossRefPubMedGoogle Scholar
  88. Preti A, Melis M, Siddi S, Vellante M, Doneddu G, Fadda R (2014) Oxytocin and autism: a systematic review of randomized controlled trials. J Child Adolesc Psychopharmacol 24(2):54–68. doi: 10.1089/cap.2013.0040CrossRefPubMedGoogle Scholar
  89. Rasalam AD, Hailey H, Williams JH, Moore SJ, Turnpenny PD, Lloyd DJ, Dean JC (2005) Characteristics of fetal anticonvulsant syndrome associated autistic disorder. Dev Med Child Neurol 47(8):551–555CrossRefPubMedGoogle Scholar
  90. Reichow B, Wolery M (2009) Comprehensive synthesis of early intensive behavioral interventions for young children with autism based on the UCLA young autism project model. J Autism Dev Disord 39(1):23–41. doi: 10.1007/s10803-008-0596-0CrossRefPubMedGoogle Scholar
  91. Rivera C, Voipio J, Payne JA, Ruusuvuori E, Lahtinen H, Lamsa K, Pirvola U, Saarma M, Kaila K (1999) The K+/Cl− co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature 397(6716):251–255. doi: 10.1038/16697CrossRefPubMedGoogle Scholar
  92. Rodenas-Cuadrado P, Ho J, Vernes SC (2014) Shining a light on CNTNAP2: complex functions to complex disorders. Eur J Hum Genet 22(2):171–178. doi: 10.1038/ejhg.2013.100CrossRefPubMedGoogle Scholar
  93. Romano A, Tempesta B, Micioni Di Bonaventura MV, Gaetani S (2015) From autism to eating disorders and more: the role of oxytocin in neuropsychiatric disorders. Front Neurosci 9:497. doi: 10.3389/fnins.2015.00497CrossRefPubMedPubMedCentralGoogle Scholar
  94. Ronesi JA, Collins KA, Hays SA, Tsai NP, Guo W, Birnbaum SG, Hu JH, Worley PF, Gibson JR, Huber KM (2012) Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome. Nat Neurosci 15(3):431–440, S431. doi: 10.1038/nn.3033CrossRefPubMedPubMedCentralGoogle Scholar
  95. Sabatier N, Leng G, Menzies J (2013) Oxytocin, feeding, and satiety. Front Endocrinol 4:35. doi: 10.3389/fendo.2013.00035CrossRefGoogle Scholar
  96. 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.2010.12.022CrossRefPubMedPubMedCentralGoogle Scholar
  97. Sala M, Braida D, Donzelli A, Martucci R, Busnelli M, Bulgheroni E, Rubino T, Parolaro D, Nishimori K, Chini B (2013) Mice heterozygous for the oxytocin receptor gene (Oxtr(+/−)) show impaired social behaviour but not increased aggression or cognitive inflexibility: evidence of a selective haploinsufficiency gene effect. J Neuroendocrinol 25(2):107–118. doi: 10.1111/j.1365-2826.2012.02385.xCrossRefPubMedPubMedCentralGoogle Scholar
  98. Schaller F, Watrin F, Sturny R, Massacrier A, Szepetowski P, Muscatelli F (2010) A single postnatal injection of oxytocin rescues the lethal feeding behaviour in mouse newborns deficient for the imprinted Magel2 gene. Hum Mol Genet 19(24):4895–4905. doi: 10.1093/hmg/ddq424CrossRefPubMedGoogle Scholar
  99. Scott-Van Zeeland AA, Abrahams BS, Alvarez-Retuerto AI, Sonnenblick LI, Rudie JD, Ghahremani D, Mumford JA, Poldrack RA, Dapretto M, Geschwind DH, Bookheimer SY (2010) Altered functional connectivity in frontal lobe circuits is associated with variation in the autism risk gene CNTNAP2. Sci Transl Med 2(56):56ra80. doi: 10.1126/scitranslmed.3001344CrossRefPubMedPubMedCentralGoogle Scholar
  100. Seida JK, Ospina MB, Karkhaneh M, Hartling L, Smith V, Clark B (2009) Systematic reviews of psychosocial interventions for autism: an umbrella review. Dev Med Child Neurol 51(2):95–104. doi: 10.1111/j.1469-8749.2008.03211.xCrossRefPubMedGoogle Scholar
  101. Sidorov MS, Auerbach BD, Bear MF (2013) Fragile X mental retardation protein and synaptic plasticity. Mol Brain 6:15. doi: 10.1186/1756-6606-6-15CrossRefPubMedPubMedCentralGoogle Scholar
  102. Strauss KA, Puffenberger EG, Huentelman MJ, Gottlieb S, Dobrin SE, Parod JM, Stephan DA, Morton DH (2006) Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. N Engl J Med 354(13):1370–1377. doi: 10.1056/NEJMoa052773CrossRefPubMedGoogle Scholar
  103. Swaab DF, Purba JS, Hofman MA (1995) Alterations in the hypothalamic paraventricular nucleus and its oxytocin neurons (putative satiety cells) in Prader-Willi-syndrome – a study of 5 cases. J Clin Endocrinol Metabol 80(2):573–579. doi: 10.1210/Jc.80.2.573CrossRefGoogle Scholar
  104. 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 U S A 102(44):16096–16101. doi: 10.1073/pnas.0505312102CrossRefPubMedPubMedCentralGoogle Scholar
  105. Tan GC, Doke TF, Ashburner J, Wood NW, Frackowiak RS (2010) Normal variation in fronto-occipital circuitry and cerebellar structure with an autism-associated polymorphism of CNTNAP2. NeuroImage 53(3):1030–1042. doi: 10.1016/j.neuroimage.2010.02.018CrossRefPubMedPubMedCentralGoogle Scholar
  106. 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.2013.04.038CrossRefPubMedPubMedCentralGoogle Scholar
  107. Teng BL, Nikolova VD, Riddick NV, Agster KL, Crowley JJ, Baker LK, Koller BH, Pedersen CA, Jarstfer MB, Moy SS (2016) Reversal of social deficits by subchronic oxytocin in two autism mouse models. Neuropharmacology 105:61–71. doi: 10.1016/j.neuropharm.2015.12.025CrossRefPubMedGoogle Scholar
  108. Tsujino N, Nakatani Y, Seki Y, Nakasato A, Nakamura M, Sugawara M, Arita H (2007) Abnormality of circadian rhythm accompanied by an increase in frontal cortex serotonin in animal model of autism. Neurosci Res 57(2):289–295. doi: 10.1016/j.neures.2006.10.018CrossRefPubMedGoogle Scholar
  109. Tyzio R, Cossart R, Khalilov I, Minlebaev M, Hubner CA, Represa A, Ben-Ari Y, Khazipov R (2006) Maternal oxytocin triggers a transient inhibitory switch in GABA signaling in the fetal brain during delivery. Science 314(5806):1788–1792. doi: 10.1126/science.1133212CrossRefPubMedGoogle Scholar
  110. Tyzio R, Nardou R, Ferrari DC, Tsintsadze T, Shahrokhi A, Eftekhari S, Khalilov I, Tsintsadze V, Brouchoud C, Chazal G, Lemonnier E, Lozovaya N, Burnashev N, Ben-Ari Y (2014) Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring. Science 343(6171):675–679. doi: 10.1126/science.1247190CrossRefPubMedGoogle Scholar
  111. Veltman MW, Craig EE, Bolton PF (2005) Autism spectrum disorders in Prader-Willi and Angelman syndromes: a systematic review. Psychiatr Genet 15(4):243–254CrossRefPubMedGoogle Scholar
  112. Warren Z, Veenstra-Vander Weele J, Stone W, Bruzek JL, Nahmias AS, Foss-Feig JH, Jerome RN, Krishnaswami S, Sathe NA, Glasser AM, Surawicz T, McPheeters ML (2011) AHRQ comparative effectiveness reviews: therapies for children with autism spectrum disorders. Agency for Healthcare Research and Quality, RockvilleGoogle Scholar
  113. Williams G, King J, Cunningham M, Stephan M, Kerr B, Hersh JH (2001) Fetal valproate syndrome and autism: additional evidence of an association. Dev Med Child Neurol 43(3):202–206CrossRefPubMedGoogle Scholar
  114. Yashiro K, Riday TT, Condon KH, Roberts AC, Bernardo DR, Prakash R, Weinberg RJ, Ehlers MD, Philpot BD (2009) Ube3a is required for experience-dependent maturation of the neocortex. Nat Neurosci 12(6):777–783. doi: 10.1038/nn.2327CrossRefPubMedPubMedCentralGoogle Scholar
  115. Yeo M, Berglund K, Augustine G, Liedtke W (2009) Novel repression of Kcc2 transcription by REST-RE-1 controls developmental switch in neuronal chloride. J Neurosci 29(46):14652–14662. doi: 10.1523/JNEUROSCI.2934-09.2009CrossRefPubMedPubMedCentralGoogle Scholar
  116. Yizhar O, Fenno LE, Prigge M, Schneider F, Davidson TJ, O’Shea DJ, Sohal VS, Goshen I, Finkelstein J, Paz JT, Stehfest K, Fudim R, Ramakrishnan C, Huguenard JR, Hegemann P, Deisseroth K (2011) Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 477(7363):171–178. doi: 10.1038/nature10360CrossRefPubMedPubMedCentralGoogle Scholar
  117. Yochum CL, Dowling P, Reuhl KR, Wagner GC, Ming X (2008) VPA-induced apoptosis and behavioral deficits in neonatal mice. Brain Res 1203:126–132. doi: 10.1016/j.brainres.2008.01.055CrossRefPubMedGoogle Scholar
  118. Zhang YQ, Bailey AM, Matthies HJ, Renden RB, Smith MA, Speese SD, Rubin GM, Broadie K (2001) Drosophila Fragile X-related gene regulates the MAP 1B homolog Futsch to control synaptic structure and function. Cell 107(5):591–603CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Sagol Department of NeurobiologyThe University of HaifaHaifaIsrael
  2. 2.Seaver Autism Center for Research and TreatmentIcahn School of Medicine at Mount SinaiNew YorkUSA
  3. 3.Department of PsychiatryIcahn School of Medicine at Mount SinaiNew YorkUSA

Personalised recommendations