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 homologue of CNTNAP2, in which mutant forms cause Cortical Dysplasia and Focal Epilepsy syndrome (CDFE), displays many features parallel to the human disorder. Since CDFE has high penetrance for autism spectrum disorder (ASD) we performed an in vivo screen for drugs that treat 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.

Plasma Oxytocin and Arginine-Vasopressin Levels in Children with Autism Spectrum Disorder in China: Associations with Symptoms

“…A higher OXT content in the hypothalamus has been reported in BTBR mice, a validated model of ASD [12]. Cntnap2 (contactin-associated proteinlike 2) gene-knockout mice display autistic-like behaviors, and have reduced OXT expression in the PVN and an overall reduction in brain OXT levels [13], while exogenous OXT treatment partially restores normal function of the OXT system and leads to improved social behaviors [13,14]. Human studies have focused on pharmacological administration and the measurement of plasma neuropeptides, mainly of OXT.…”

“…An abnormal brain OXT system has been found in several mouse models of autism [11][12][13]. For example, neonatal mice deficient in Magel2 (MAGE family member L2), which may be involved in ASD, have significantly reduced OXT in the hypothalamus [11].…”

Neuroscience: The hard science of oxytocin

“…Some of the clearest evidence emerged in February, from a team led by neurogeneticist Daniel Geschwind of the University of California, Los Angeles. The group showed that mice that lacked a working copy of the Cntnap2 gene -which has been implicated in a small subset of human autism cases -had fewer oxytocin-containing neurons in the hypothalamus and socialized less with other mice than did control mice 15 . After receiving doses of oxytocin every day for two weeks, the mice behaved normally again.…”

Endocannabinoid signaling mediates oxytocin-driven social reward

“…2B). Lastly, and similarly to social stimulation, site-selective chemogenetic activation of oxytocin-secreting neurons in the PVN, which we previously showed to increase oxytocin transmission (23), increased anandamide mobilization in the NAc. Administration of clozapine-N-oxide (CNO) in mice engineered to express CNO receptors exclusively in oxytocinergic neurons of the PVN, strongly elevated anandamide content in the NAc, while having no effect on 2-AG ( Fig.…”