title: Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism.
abstract: Mouse models of neuropsychiatric diseases provide a platform for mechanistic understanding and development of new therapies. We previously demonstrated that knockout of the mouse homolog of CNTNAP2 (contactin-associated protein-like 2), in which mutations cause cortical dysplasia and focal epilepsy (CDFE) syndrome, displays many features that parallel those of the human disorder. Because CDFE has high penetrance for autism spectrum disorder (ASD), we performed an in vivo screen for drugs that ameliorate abnormal social behavior in Cntnap2 mutant mice and found that acute administration of the neuropeptide oxytocin improved social deficits. We found a decrease in the number of oxytocin immunoreactive neurons in the paraventricular nucleus (PVN) of the hypothalamus in mutant mice and an overall decrease in brain oxytocin levels. Administration of a selective melanocortin receptor 4 agonist, which causes endogenous oxytocin release, also acutely rescued the social deficits, an effect blocked by an oxytocin antagonist. We confirmed that oxytocin neurons mediated the behavioral improvement by activating endogenous oxytocin neurons in the paraventricular hypothalamus with Designer Receptors Exclusively Activated by Designer Drugs (DREADD). Last, we showed that chronic early postnatal treatment with oxytocin led to more lasting behavioral recovery and restored oxytocin immunoreactivity in the PVN. These data demonstrate dysregulation of the oxytocin system in Cntnap2 knockout mice and suggest that there may be critical developmental windows for optimal treatment to rectify this deficit.
authors.affiliation: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Center for Autism Research and Treatment and Center for Neurobehavioral Genetics, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Peñagarikano
authors.affiliation: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: María T
authors.initials: MT
authors.lastname: Lázaro
authors.affiliation: Center for Neurobehavioral Genetics, Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Lu
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Aaron
authors.initials: A
authors.lastname: Gordon
authors.affiliation: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Dong
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Hoa A
authors.initials: HA
authors.lastname: Lam
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Elior
authors.initials: E
authors.lastname: Peles
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Nigel T
authors.initials: NT
authors.lastname: Maidment
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Niall P
authors.initials: NP
authors.lastname: Murphy
authors.affiliation: Center for Neurobehavioral Genetics, Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: X William
authors.initials: XW
authors.lastname: Yang
authors.affiliation: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Integrative Center for Learning and Memory, University of California, Los Angeles, Los Angeles, CA 90095, USA. West Los Angeles VA Medical Center, Los Angeles, CA 90073, USA.
authors.forename: Peyman
authors.initials: P
authors.lastname: Golshani
authors.affiliation: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Center for Autism Research and Treatment and Center for Neurobehavioral Genetics, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90095, USA. Center for Neurobehavioral Genetics, Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA. dhg@ucla.edu.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001321:Autistic Disorder / Q000188:drug therapy* / Q000473:pathology; D001522:Behavior, Animal; D004195:Disease Models, Animal; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010121:Oxytocin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000473:pathology; D012919:Social Behavior
chemical_list: C568163:CNTNAP2 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010121:Oxytocin