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

Authors: Peñagarikano, Olga  Lázaro, María T  Lu, Xiao-Hong  Gordon, Aaron  Dong, Hongmei  Lam, Hoa A  Peles, Elior  Maidment, Nigel T  Murphy, Niall P  Yang, X William  Golshani, Peyman  Geschwind, Daniel H 
Citation: Peñagarikano O, etal., Sci Transl Med. 2015 Jan 21;7(271):271ra8. doi: 10.1126/scitranslmed.3010257.
Pubmed: (View Article at PubMed) PMID:25609168
DOI: Full-text: DOI:10.1126/scitranslmed.3010257

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.

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RGD ID: 13450908
Created: 2017-11-08
Species: All species
Last Modified: 2017-11-08
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