Advertisement

Pharmacologic Rescue of Impaired Cognitive Flexibility, Social Deficits, Increased Aggression, and Seizure Susceptibility in Oxytocin Receptor Null Mice: A Neurobehavioral Model of Autism

Published:February 09, 2011DOI:https://doi.org/10.1016/j.biopsych.2010.12.022

      Background

      Oxytocin (OT) has been suggested as a treatment to improve social behavior in autistic patients. Accordingly, the OT (Oxt−/−) and the OT receptor null mice (Oxtr−/−) display autistic-like deficits in social behavior, increased aggression, and reduced ultrasonic vocalization.

      Methods

      Oxtr−/− mice were characterized for general health, sociability, social novelty, cognitive flexibility, aggression, and seizure susceptibility. Because vasopressin (AVP) and OT cooperate in controlling social behavior, learning, and aggression, they were tested for possible rescue of the impaired behaviors. Primary hyppocampal cultures from Oxtr+/+ and Oxtr−/− mouse embryos were established to investigate the balance between gamma-aminobutyric acid (GABA) and glutamate synapses and the expression levels of OT and AVP (V1a) receptors were determined by autoradiography.

      Results

      Oxtr−/− mice display two additional, highly relevant, phenotypic characteristics: 1) a resistance to change in a learned pattern of behavior, comparable to restricted interests and repetitive behavior in autism, and 2) an increased susceptibility to seizures, a frequent and clinically relevant symptom of autism. We also show that intracerebral administration of both OT and AVP lowers aggression and fully reverts social and learning defects by acting on V1a receptors and that seizure susceptibility is antagonized by peripherally administered OT. Finally, we detect a decreased ratio of GABA–ergic versus total presynapses in hippocampal neurons of Oxtr−/− mice.

      Conclusions

      Autistic-like symptoms are rescued on administration of AVP and OT to young Oxtr−/− adult animals. The Oxtr−/− mouse is thus instrumental to investigate the neurochemical and synaptic abnormalities underlying autistic-like disturbances and to test new strategies of pharmacologic intervention.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Macdonald K.
        • Macdonald T.M.
        The peptide that binds: A systematic review of oxytocin and its prosocial effects in humans.
        Harv Rev Psychiatry. 2010; 18: 1-21
        • McEwen B.B.
        General introduction to vasopressin and oxytocin: Structure/metabolism, evolutionary aspects, neural pathway/receptor distribution, and functional aspects relevant to memory processing.
        Adv Pharmacol. 2004; 50: 1-50
        • Donaldson Z.R.
        • Young L.J.
        Oxytocin, vasopressin, and the neurogenetics of sociality.
        Science. 2008; 322: 900-904
        • Lee H.J.
        • Macbeth A.H.
        Oxytocin: The great facilitator of life.
        Prog Neurobiol. 2009; 88 (Pagani JH, Young WS 3rd (2009)): 127-151
        • Choleris E.
        • Clipperton-Allen A.E.
        • Phan A.
        • Kavaliers M.
        Neuroendocrinology of social information processing in rats and mice.
        Front Neuroendocrinol. 2009; 30: 442-459
        • Insel T.R.
        The challenge of translation in social neuroscience: A review of oxytocin, vasopressin, and affiliative behavior.
        Neuron. 2010; 65: 768-779
        • Insel T.R.
        • O'Brien D.J.
        • Leckman J.F.
        Oxytocin, vasopressin, and autism: Is there a connection?.
        Biol Psychiatry. 1999; 45: 145-157
        • Carter C.S.
        Sex differences in oxytocin and vasopressin: Implications for autism spectrum disorders?.
        Behav Brain Res. 2007; 176: 170-186
        • Hollander E.
        • Novotny S.
        • Hanratty M.
        • Yaffe R.
        • DeCaria C.M.
        • Aronowitz B.R.
        • Mosovich S.
        Oxytocin infusion reduces repetitive behaviors in adults with autistic and Asperger's disorders.
        Neuropsychopharmacology. 2003; 28: 193-198
        • 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: 498-503
        • Guastella A.J.
        • Einfeld S.L.
        • Gray K.M.
        • Rinehart N.J.
        • Tonge B.J.
        • Lambert T.J.
        • Hickie I.B.
        Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders.
        Biol Psychiatry. 2010; 67: 692-694
        • Andari E.
        • Duhamel J.R.
        • 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: 4389-4394
        • Tyzio R.
        • Cossart R.
        • Khalilov I.
        • Minlebaev M.
        • Hubner C.A.
        • Represa A.
        • et al.
        Maternal oxytocin triggers a transient inhibitory switch in GABA signaling in the fetal brain during delivery.
        Science. 2006; 314: 1788-1792
        • Tomizawa K.
        • Iga N.
        • Lu Y.F.
        • Moriwaki A.
        • Matsushita M.
        • Li S.T.
        • et al.
        Oxytocin improves long-lasting spatial memory during motherhood through MAP kinase cascade.
        Nat Neurosci. 2003; 6: 384-390
        • Takayanagi Y.
        • Yoshida M.
        • Bielsky I.F.
        • Ross H.E.
        • 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: 16096-16101
        • Moy S.S.
        • Nadler J.J.
        • Perez A.
        • Barbaro R.P.
        • Johns J.M.
        • Magnuson T.R.
        • et al.
        Sociability and preference for social novelty in five inbred strains: An approach to assess autistic-like behavior in mice.
        Genes Brain Behav. 2004; 3: 287-302
        • Tordjman S.
        • Carlier M.
        • Cohen D.
        • Cesselin F.
        • Bourgoin S.
        • Colas-Linhart N.
        • et al.
        Aggression and the three opioid families (endorphins, enkephalins, and dynorphins) in mice.
        Behav Genet. 2003; 33: 529-536
        • Manfredi I.
        • Zani A.D.
        • Rampoldi L.
        • Pegorini S.
        • Bernascone I.
        • Moretti M.
        • et al.
        Expression of mutant beta2 nicotinic receptors during development is crucial for epileptogenesis.
        Hum Mol Genet. 2009; 18: 1075-1088
        • Nosten-Bertrand M.
        • Kappeler C.
        • Dinocourt C.
        • Denis C.
        • Germain J.
        • Phan D.
        • et al.
        Epilepsy in Dcx knockout mice associated with discrete lamination defects and enhanced excitability in the hippocampus.
        PLoS ONE. 2008; 3: e2473
        • Gard P.R.
        • Daw P.
        • Mashhour Z.S.
        • Tran P.
        Interactions of angiotensin IV and oxytocin on behaviour in mice.
        J Renin Angiotensin Aldosterone Syst. 2007; 8: 133-138
        • Kaech S.
        • Banker G.
        Culturing hippocampal neurons.
        Nat Protoc. 2006; 1: 2406-2415
        • Lentini D.
        • Guzzi F.
        • Pimpinelli F.
        • Zaninetti R.
        • Cassetti A.
        • Coco S.
        • et al.
        Polarization of caveolins and caveolae during migration of immortalized neurons.
        J Neurochem. 2008; 104: 514-523
        • Francis D.D.
        • Young L.J.
        • Meaney M.J.
        • Insel T.R.
        Naturally occurring differences in maternal care are associated with the expression of oxytocin and vasopressin (V1a) receptors: Gender differences.
        J Neuroendocrinol. 2002; 14: 349-353
        • Elands J.
        • Barberis C.
        • Jard S.
        • Tribollet E.
        • Dreifuss J.
        • Bankowski K.
        • et al.
        125Ilabelled d(CH2)5[Tyr(Me)2,Thr4,Tyr-NH29]OVT: A selective oxytocin receptor ligand.
        Eur J Pharmacol. 1988; 147: 197-207
        • Schmidt A.
        • Audigier S.
        • Barberis C.
        • Jard S.
        • Manning M.
        • Kolodziejczyk A.S.
        • Sawyer W.H.
        A radioiodinated linear vasopressin antagonist: A ligand with high affinity and specificity for V1a receptors.
        FEBS Lett. 1991; 282: 77-81
        • Crawley J.N.
        Designing mouse behavioral tasks relevant to autistic-like behaviors.
        Ment Retard Dev Disabil Res Rev. 2004; 10: 248-258
        • Tuchman R.
        • Rapin I.
        Epilepsy in autism.
        Lancet Neurol. 2002; 1: 352-358
        • Gabis L.
        • Pomeroy J.
        • Andriola M.R.
        Autism and epilepsy: Cause, consequence, comorbidity, or coincidence?.
        Epilepsy Behav. 2005; 7: 652-656
        • Dotti C.G.
        • Sullivan C.A.
        • Banker G.A.
        The establishment of polarity by hippocampal neurons in culture.
        J Neurosci. 1988; 8: 1454-1468
        • Bartlett W.P.
        • Banker G.A.
        An electron microscopic study of the development of axons and dendrites by hippocampal neurons in culture. II. Synaptic relationships.
        J Neurosci. 1984; 4: 1954-1965
        • Grabrucker A.
        • Vaida B.
        • Bockmann J.
        • Boeckers T.M.
        Synaptogenesis of hippocampal neurons in primary cell culture.
        Cell Tissue Res. 2009; 338: 333-341
        • Benson D.L.
        • Watkins F.H.
        • Steward O.
        • Banker G.
        Characterization of GABAergic neurons in hippocampal cell cultures.
        J Neurocytol. 1994; 23: 279-295
        • Chini B.
        • Mouillac B.
        • Balestre M.
        • Trumpp-Kallmeyer S.
        • Hoflack J.
        • Hibert M.
        • et al.
        Two aromatic residues regulate the response of the human oxytocin receptor to the partial agonist arginine vasopressin.
        FEBS Lett. 1996; 397: 201-206
        • Tribollet E.
        Vasopressin and oxytocin receptors in the rat brain.
        in: Bjorklund A. Hokfelt T. Kuhar M.J. Handbook of Chemical Neuroanatomy. Vol. 4. Elsevier, Amsterdam1992: 289-320
        • Johnson A.E.
        • Audigier S.
        • Rossi F.
        • Jard S.
        • Tribollet E.
        • Barberis C.
        Localization and characterization of vasopressin binding sites in the rat brain using an iodinated linear AVP antagonist.
        Brain Res. 1993; 622: 9-16
        • Tuchman R.
        • Moshe S.L.
        • Rapin I.
        Convulsing toward the pathophysiology of autism.
        Brain Dev. 2009; 31: 95-103
        • Zoghbi H.Y.
        Postnatal neurodevelopmental disorders: Meeting at the synapse?.
        Science. 2003; 302: 826-830
        • Walsh C.A.
        • Morrow E.M.
        • Rubenstein J.L.
        Autism and brain development.
        Cell. 2008; 135: 396-400
        • Geschwind D.H.
        • Levitt P.
        Autism spectrum disorders: Developmental disconnection syndromes.
        Curr Opin Neurobiol. 2007; 17: 103-111
        • Treffert D.A.
        The savant syndrome: An extraordinary condition.
        Philos Trans R Soc Lond B Biol Sci. 2009; 364: 1351-1357
        • Ferguson J.N.
        • Young L.J.
        • Hearn E.F.
        • Matzuk M.M.
        • Insel T.R.
        • Winslow J.T.
        Social amnesia in mice lacking the oxytocin gene.
        Nat Genet. 2000; 25: 284-288
        • Jin D.
        • Liu H.X.
        • Hirai H.
        • Torashima T.
        • Nagai T.
        • Lopatina O.
        • et al.
        CD38 is critical for social behaviour by regulating oxytocin secretion.
        Nature. 2007; 446: 41-45
        • Landgraf R.
        • Gerstberger R.
        • Montkowski A.
        • Probst J.C.
        • Wotjak C.T.
        • Holsboer F.
        • Engelmann M.
        V1 vasopressin receptor antisense oligodeoxynucleotide into septum reduces vasopressin binding, social discrimination abilities, and anxiety-related behavior in rats.
        J Neurosci. 1995; 15: 4250-4258
        • Bielsky I.F.
        • Hu S.B.
        • Ren X.
        • Terwilliger E.F.
        • Young L.J.
        The V1a vasopressin receptor is necessary and sufficient for normal social recognition: A gene replacement study.
        Neuron. 2005; 47: 503-513
        • Ferguson J.N.
        • Aldag J.M.
        • Insel T.R.
        • Young L.J.
        Oxytocin in the medial amygdala is essential for social recognition in the mouse.
        J Neurosci. 2001; 21: 8278-8285
        • Young L.J.
        • Murphy Young A.Z.
        • Hammock E.A.
        Anatomy and neurochemistry of the pair bond.
        J Comp Neurol. 2005; 493: 51-57
        • Ehninger D.
        • Han S.
        • Shilyansky C.
        • Zhou Y.
        • Li W.
        • Kwiatkowski D.J.
        • et al.
        Reversal of learning deficits in a TscII+/−mouse model of tuberous sclerosis.
        Nat Med. 2008; 14: 843-848
        • Winslow J.T.
        • Hastings N.
        • Carter C.S.
        • Harbaugh C.R.
        • Insel T.R.
        A role for central vasopressin in pair bonding in monogamous prairie voles.
        Nature. 1993; 365: 545-548
        • Gobrogge K.L.
        • Liu Y.
        • Young L.J.
        • Wang Z.
        Anterior hypothalamic vasopressin regulates pair-bonding and drug-induced aggression in a monogamous rodent.
        Proc Natl Acad Sci U S A. 2009; 106: 19144-19149
        • Ferris C.F.
        • Potegal M.
        Vasopressin receptor blockade in the anterior hypothalamus suppresses aggression in hamsters.
        Physiol Behav. 1988; 44: 235-239
        • Wersinger S.R.
        • Caldwell H.K.
        • Martinez L.
        • Gold P.
        • Hu S.B.
        • Young 3rd, W.S.
        Vasopressin 1a receptor knockout mice have a subtle olfactory deficit but normal aggression.
        Genes Brain Behav. 2007; 6: 540-551
        • Siegel A.
        • Bhatt S.
        • Bhatt R.
        • Zalcman S.S.
        The neurobiological bases for development of pharmacological treatments of aggressive disorders.
        Curr Neuropharmacol. 2007; 5: 135-147
        • Yoshida M.
        • Takayanagi Y.
        • Inoue K.
        • Kimura T.
        • Young L.J.
        • Onaka T.
        • Nishimori K.
        Evidence that oxytocin exerts anxiolytic effects via oxytocin receptor expressed in serotonergic neurons in mice.
        J Neurosci. 2009; 29: 2259-2271
        • Theodosis D.T.
        • Koksma J.J.
        • Trailin A.
        • Langle S.L.
        • Piet R.
        • Lodder J.C.
        • et al.
        Oxytocin and estrogen promote rapid formation of functional GABA synapses in the adult supraoptic nucleus.
        Mol Cell Neurosci. 2006; 31: 785-794
        • Oliet S.H.
        • Piet R.
        • Poulain D.A.
        • Theodosis D.T.
        Glial modulation of synaptic transmission: Insights from the supraoptic nucleus of the hypothalamus.
        Glia. 2004; 47: 258-267
        • Morellini F.
        • Sivukhina E.
        • Stoenica L.
        • Oulianova E.
        • Bukalo O.
        • Jakovcevski I.
        • et al.
        Improved reversal learning and working memory and enhanced reactivity to novelty in mice with enhanced GABAergic innervation in the dentate gyrus.
        Cereb Cortex. 2010; 20: 2712-2727
        • Floresco S.B.
        • Zhang Y.
        • Enomoto T.
        Neural circuits subserving behavioral flexibility and their relevance to schizophrenia.
        Behav Brain Res. 2009; 204: 396-409
        • Todeschin A.S.
        • Winkelmann-Duarte E.C.
        • Jacob M.H.
        • Aranda B.C.
        • Jacobs S.
        • Fernandes M.C.
        • et al.
        Effects of neonatal handling on social memory, social interaction, and number of oxytocin and vasopressin neurons in rats.
        Horm Behav. 2009; 56: 93-100
        • Curley J.P.
        • Davidson S.
        • Bateson P.
        • Champagne F.A.
        Social enrichment during postnatal development induces transgenerational effects on emotional and reproductive behavior in mice.
        Front Behav Neurosci. 2009; 3: 25

      Linked Article

      • A Complicated Picture of Oxytocin Action in the Central Nervous System Revealed
        Biological PsychiatryVol. 69Issue 9
        • Preview
          It has been difficult not to notice the massive growth of public awareness and research funding that has steadily increased around autism spectrum disorders (ASD) over the past 10 years. With recent epidemiology studies revealing dramatic rises in prevalence rates that now rival other psychiatric disorders such as schizophrenia, the impact on public health systems and realization of unmet medical needs in ASD has created a growing expectation for improved diagnosis and treatments. Historically considered a backwater of psychiatric drug development, ASD has now captured interest from the pharmaceutical industry (1), which sees significant opportunity in the tractability of a rapidly emerging science around ASD.
        • Full-Text
        • PDF