Ossitocina, vasopressina e autismo: nuovi target e strategie terapeutiche - Conclusioni


    L’effetto dell’OT nel favorire i contatti e le relazioni sociali è al momento di grande interesse per il possibile impiego di questo peptide in condizioni neuropsichiatriche e del neurosviluppo caratterizzate da deficit nelle relazioni socio/emotive.

    Inoltre, i nostri studi recenti nell’animale indicano che questi peptidi potrebbero avere importanti effetti anche nel modulare la flessibilità cognitiva e nel ridurre il rischio epilettico (37).

    Di grande rilevanza, infine, è la capacità di questi neuro peptidi di agire anche in animali adulti (37), indicando che il sistema OT/AVP è altamente plastico e capace di modulare l’attività di processi cognitivi complessi anche al termine dello sviluppo.

    Lo studio di questi meccanismi e processi, così come lo sviluppo di nuovi analoghi OT/AVP, più potenti e selettivi ed in grado di superare la barriera emato-encefalica, è al momento un attivo e promettente campo di ricerca per lo sviluppo, nel prossimo futuro, di nuove strategie terapeutiche per il trattamento della sintomatologia autistica.

    Ringraziamenti Questo lavoro é stato possibile grazie al contributo della Fondazione Cariplo (Grant 2008.2314).

    Biliografia

    1. Gimpl G, Fahrenholz F. The oxytocin receptor system: structure, function, and regulation. Physiol Rev 2001;81(2):629-83.

    2. Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E. Oxytocin increases trust in humans. Nature 2005;435(7042):673-6.

    3. Zak PJ, Kurzban R, Matzner WT. Oxytocin is associated with human trustworthiness. Horm Behav 2005;48(5):522-7.

    4. Zak PJ, Stanton AA, Ahmadi S. Oxytocin increases generosity in humans. PLoS One 2007;2(11):e1128.

    5. Bartz JA, Zaki J, Bolger N, Hollander E, Ludwig NN, Kolevzon A, et al. Oxytocin selectively improves empathic accuracy. Psychol Sci 2010;21(10):1426-8.

    6. De Dreu CK, Greer LL, Handgraaf MJ, Shalvi S, Van Kleef GA, Baas M, et al. The neuropeptide oxytocin regulates parochial altruism in intergroup conflict among humans. Science 2010;328(5984):1408-11.

    7. Domes G, Heinrichs M, Michel A, Berger C, Herpertz SC. Oxytocin improves "mind-reading" in humans. Biol Psychiatry 2007;61(6):731-3.

    8. Guastella AJ, Einfeld SL, Gray KM, Rinehart NJ, Tonge BJ, Lambert TJ, et al. Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders. Biol Psychiatry 2010;67(7):692-4.

    9. Savaskan E, Ehrhardt R, Schulz A, Walter M, Schachinger H. Post-learning intranasal oxytocin modulates human memory for facial identity. Psychoneuroendocrinology 2008;33(3):368-74.

    10.Guastella AJ, Mitchell PB, Dadds MR. Oxytocin increases gaze to the eye region of human faces. Biol Psychiatry 2008;63(1):3-5.

    11.Campbell A. Attachment, aggression and affiliation: the role of oxytocin in female social behavior. Biol Psychol 2008;77(1):1-10.

    12.Heinrichs M, Domes G. Neuropeptides and social behaviour: effects of oxytocin and vasopressin in humans. Prog Brain Res 2008;170:337-50.

    13.Leckman JF, Goodman WK, North WG, Chappell PB, Price LH, Pauls DL, et al. Elevated cerebrospinal fluid levels of oxytocin in obsessive-compulsive disorder. Comparison with Tourette's syndrome and healthy controls. Arch Gen Psychiatry 1994;51(10):782-92.

    14.Martin A, State M, Anderson GM, Kaye WM, Hanchett JM, McConaha CW, et al. Cerebrospinal fluid levels of oxytocin in Prader-Willi syndrome: a preliminary report. Biol Psychiatry 1998;44(12):1349-52.

    15.Goldman M, Marlow-O'Connor M, Torres I, Carter CS. Diminished plasma oxytocin in schizophrenic patients with neuroendocrine dysfunction and emotional deficits. Schizophr Res 2008;98(1-3):247-55.

    16.Modahl C, Green L, Fein D, Morris M, Waterhouse L, Feinstein C, et al. Plasma oxytocin levels in autistic children. Biol Psychiatry 1998;43(4):270-7.

    17.Green L, Fein D, Modahl C, Feinstein C, Waterhouse L, Morris M. Oxytocin and autistic disorder: alterations in peptide forms. Biol Psychiatry 2001;50(8):609-13.

    18.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. Biol Psychiatry 2005;58(1):74-7.

    19.Yrigollen CM, Han SS, Kochetkova A, Babitz T, Chang JT, Volkmar FR, et al. Genes controlling affiliative behavior as candidate genes for autism. Biol Psychiatry 2008;63(10):911-6.

    20.Gregory SG, Connelly JJ, Towers AJ, Johnson J, Biscocho D, Markunas CA, et al. Genomic and epigenetic evidence for oxytocin receptor deficiency in autism. BMC Med 2009;7:62.

    21.Hollander E, Novotny S, Hanratty M, Yaffe R, DeCaria CM, Aronowitz BR, et al. Oxytocin infusion reduces repetitive behaviors in adults with autistic and Asperger's disorders. Neuropsychopharmacology 2003;28(1):193-8.

    22.Hollander E, Bartz J, Chaplin W, Phillips A, Sumner J, Soorya L, et al. Oxytocin increases retention of social cognition in autism. Biol Psychiatry 2007;61(4):498-503.

    23.Andari E, Duhamel JR, Zalla T, Herbrecht E, Leboyer M, Sirigu A. Promoting social behavior with oxytocin in high-functioning autism spectrum disorders. Proc Natl Acad Sci U S A 2010;107(9):4389-94.

    24.Crawley JN. Mouse behavioral assays relevant to the symptoms of autism. Brain Pathol 2007;17(4):448-59.

    25.Scattoni ML, Crawley J, Ricceri L. Ultrasonic vocalizations: a tool for behavioural phenotyping of mouse models of neurodevelopmental disorders. Neurosci Biobehav Rev 2009;33(4):508-15.

    26.Crawley JN. Designing mouse behavioral tasks relevant to autistic-like behaviors. Ment Retard Dev Disabil Res Rev 2004;10(4):248-58.

    27.Moy SS, Nadler JJ, Young NB, Perez A, Holloway LP, Barbaro RP, et al. Mouse behavioral tasks relevant to autism: phenotypes of 10 inbred strains. Behav Brain Res 2007;176(1):4-20.

    28.Insel TR, O'Brien DJ, Leckman JF. Oxytocin, vasopressin, and autism: is there a connection? Biol Psychiatry 1999;45(2):145-57.

    29.Ferguson JN, Young LJ, Hearn EF, Matzuk MM, Insel TR, Winslow JT. Social amnesia in mice lacking the oxytocin gene. Nat Genet 2000;25(3):284-8.

    30.Winslow JT, Insel TR. The social deficits of the oxytocin knockout mouse. Neuropeptides 2002;36(2-3):221-9.

    31.Ferguson JN, Aldag JM, Insel TR, Young LJ. Oxytocin in the medial amygdala is essential for social recognition in the mouse. J Neurosci 2001;21(20):8278-85.

    32.Winslow JT, Hearn EF, Ferguson J, Young LJ, Matzuk MM, Insel TR. Infant vocalization, adult aggression, and fear behavior of an oxytocin null mutant mouse. Horm Behav 2000;37(2):145-55.

    33.Jin D, Liu HX, Hirai H, Torashima T, Nagai T, Lopatina O, et al. CD38 is critical for social behaviour by regulating oxytocin secretion. Nature 2007;446(7131):41-5.

    34.Nishimori K, Young LJ, Guo Q, Wang Z, Insel TR, Matzuk MM. Oxytocin is required for nursing but is not essential for parturition or reproductive behavior. Proc Natl Acad Sci U S A 1996;93(21):11699-704.

    35.Takayanagi Y, Yoshida M, Bielsky IF, Ross HE, Kawamata M, Onaka T, et al. Pervasive social deficits, but normal parturition, in oxytocin receptor-deficient mice. Proc Natl Acad Sci U S A 2005;102(44):16096-101.

    36.Lee HJ, Caldwell HK, Macbeth AH, Young WS, 3rd. Behavioural studies using temporal and spatial inactivation of the oxytocin receptor. Prog Brain Res 2008;170:73-7.

    37.Sala M, Braida D, Lentini D, M. B, Bulgheroni E, Capurro V, et al. Pharmacological rescue of impaired cognitive flexibility, social deficits, increased aggression and seizure susceptibility in the oxytocin receptor null mice, a neurobehavioral model of autism. Biol Psychiatry 2011;in press.

    38.Kim SJ, Young LJ, Gonen D, Veenstra-VanderWeele J, Courchesne R, Courchesne E, et al. Transmission disequilibrium testing of arginine vasopressin receptor 1A (AVPR1A) polymorphisms in autism. Mol Psychiatry 2002;7(5):503-7.

    39.Wassink TH, Piven J, Vieland VJ, Pietila J, Goedken RJ, Folstein SE, et al. Examination of AVPR1a as an autism susceptibility gene. Mol Psychiatry 2004;9(10):968-72.

    40.Yirmiya N, Rosenberg C, Levi S, Salomon S, Shulman C, Nemanov L, et al. Association between the arginine vasopressin 1a receptor (AVPR1a) gene and autism in a family-based study: mediation by socialization skills. Mol Psychiatry 2006;11(5):488-94.

    41.Bielsky IF, Hu SB, Szegda KL, Westphal H, Young LJ. Profound impairment in social recognition and reduction in anxiety-like behavior in vasopressin V1a receptor knockout mice. Neuropsychopharmacology 2004;29(3):483-93.

    42.Egashira N, Mishima K, Iwasaki K, Oishi R, Fujiwara M. New topics in vasopressin receptors and approach to novel drugs: role of the vasopressin receptor in psychological and cognitive functions. J Pharmacol Sci 2009;109(1):44-9.

    43.Belmonte MK, Allen G, Beckel-Mitchener A, Boulanger LM, Carper RA, Webb SJ. Autism and abnormal development of brain connectivity. J Neurosci 2004;24(42):9228-31.

    44.Just MA, Cherkassky VL, Keller TA, Minshew NJ. Cortical activation and synchronization during sentence comprehension in high-functioning autism: evidence of underconnectivity. Brain 2004;127(Pt 8):1811-21.

    45.DiCicco-Bloom E, Lord C, Zwaigenbaum L, Courchesne E, Dager SR, Schmitz C, et al. The developmental neurobiology of autism spectrum disorder. J Neurosci 2006;26(26):6897-906.

    46.Sporns O, Tononi G, Edelman GM. Theoretical neuroanatomy: relating anatomical and functional connectivity in graphs and cortical connection matrices. Cereb Cortex 2000;10(2):127-41.

    47.McDougle CJ, Erickson CA, Stigler KA, Posey DJ. Neurochemistry in the pathophysiology of autism. J Clin Psychiatry 2005;66 Suppl 10:9-18.

    48.Tyzio R, Cossart R, Khalilov I, Minlebaev M, Hubner CA, Represa A, et al. Maternal oxytocin triggers a transient inhibitory switch in GABA signaling in the fetal brain during delivery. Science 2006;314(5806):1788-92.

    49.Theodosis DT, Koksma JJ, Trailin A, Langle SL, Piet R, Lodder JC, et al. Oxytocin and estrogen promote rapid formation of functional GABA synapses in the adult supraoptic nucleus. Mol Cell Neurosci 2006;31(4):785-94.

    50.Rubenstein JL, Merzenich MM. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav 2003;2(5):255-67.

    51.Hensch TK. Critical period plasticity in local cortical circuits. Nat Rev Neurosci 2005;6(11):877-88.

    52.Fagiolini M, Hensch TK. Inhibitory threshold for critical-period activation in primary visual cortex. Nature 2000;404(6774):183-6.

    53.Iwai Y, Fagiolini M, Obata K, Hensch TK. Rapid critical period induction by tonic inhibition in visual cortex. J Neurosci 2003;23(17):6695-702.

    54.Jamain S, Quach H, Betancur C, Rastam M, Colineaux C, Gillberg IC, et al. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet 2003;34(1):27-9.

    55.Scheiffele P, Fan J, Choih J, Fetter R, Serafini T. Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons. Cell 2000;101(6):657-69.

    56.Graf ER, Zhang X, Jin SX, Linhoff MW, Craig AM. Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins. Cell 2004;119(7):1013-26.

    57.Missler M, Zhang W, Rohlmann A, Kattenstroth G, Hammer RE, Gottmann K, et al. Alpha-neurexins couple Ca2+ channels to synaptic vesicle exocytosis. Nature 2003;423(6943):939-48.

    58.Varoqueaux F, Aramuni G, Rawson RL, Mohrmann R, Missler M, Gottmann K, et al. Neuroligins determine synapse maturation and function. Neuron 2006;51(6):741-54.

    59.Chubykin AA, Atasoy D, Etherton MR, Brose N, Kavalali ET, Gibson JR, et al. Activity-dependent validation of excitatory versus inhibitory synapses by neuroligin-1 versus neuroligin-2. Neuron 2007;54(6):919-31.

    60.Oliet SH, Piet R, Poulain DA, Theodosis DT. Glial modulation of synaptic transmission: Insights from the supraoptic nucleus of the hypothalamus. Glia 2004;47(3):258-67.

    61.Neusch C, Rozengurt N, Jacobs RE, Lester HA, Kofuji P. Kir4.1 potassium channel subunit is crucial for oligodendrocyte development and in vivo myelination. J Neurosci 2001;21(15):5429-38.

    Ossitocina, vasopressina e autismo: nuovi target e strategie terapeutiche - Introduzione

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