Research ArticleAutism

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

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Science Translational Medicine  21 Jan 2015:
Vol. 7, Issue 271, pp. 271ra8
DOI: 10.1126/scitranslmed.3010257

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Going Social

Oxytocin—a hormone that promotes mothering, trust, and social bonding in animals—seems a likely treatment for the social isolation of individuals on the autism spectrum, but tests in humans have generally proved disappointing. To delve deeper into how oxytocin affects autism symptoms, Peñagarikano et al. created a mouse mimic of one type of genetic autism, cortical dysplasia and focal epilepsy (CDFE) syndrome, by deleting the gene that is mutated in human patients. Unlike normal mouse-loving mice, CDFE mice were asocial, showing no preference for other mice over objects, but this deficit was reversed by giving them oxytocin. Further, revving up the sluggish production of their own oxytocin in the paraventricular nucleus in the hypothalamus also improved sociability. Most hopeful for patients, the authors found that giving young CDFE mice multiple doses of oxytocin just after birth produces a long-lasting improvement in oxytocin brain levels and sociability.

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.

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