Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism

Sci Transl Med 21 January 2015: 
Vol. 7, Issue 271, p. 271ra8 
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3010257

• RESEARCH ARTICLE

AUTISM

Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism

1. Olga Peñagarikano1,2, 
2. María T. Lázaro1, 
3. Xiao-Hong Lu3, 
4. Aaron Gordon4, 
5. Hongmei Dong1, 
6. Hoa A. Lam5,
7. Elior Peles4, 
8. Nigel T. Maidment5, 
9. Niall P. Murphy5, 
10. X. William Yang3, 
11. Peyman Golshani1,6,7 and
12. Daniel H. Geschwind1,2,3,*

+Author Affiliations

1. ¹Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
2. ²Center 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.
3. ³Center for Neurobehavioral Genetics, Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA.
4. ⁴Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
5. ⁵Department 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.
6. ⁶Integrative Center for Learning and Memory, University of California, Los Angeles, Los Angeles, CA 90095, USA.
7. ⁷West Los Angeles VA Medical Center, Los Angeles, CA 90073, USA.

1. ↵*Corresponding author. E-mail: dhg@ucla.edu

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 inCntnap2 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.

• Copyright © 2015, American Association for the Advancement of Science

Citation: O. Peñagarikano, M. T. Lázaro, X.-H. Lu, A. Gordon, H. Dong, H. A. Lam, E. Peles, N. T. Maidment, N. P. Murphy, X. W. Yang, P. Golshani, D. H. Geschwind, Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism. Sci. Transl. Med. 7, 271ra8 (2015).

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