Abstract
[Background] A large number of clinical researches have reported that dosing valproic acid (VPA) during pregnancy causes autism spectrum disorders (ASD) in children. We have demonstrated that mice prenatally exposed to VPA at embryonic day 12.5 (E12.5) are useful as an ASD model (Kataoka et al., Int. J. Neuropsychopharmacol. 2013; Takuma et al., Pharmacol. Biochem. Behav. 2014; Hara et al., Behav. Brain Res. 2015; Hara et al., Autism Res. 2016; Hara et al., Psychopharmacology 2017). Recent animal and clinical studies showed that oxytocin improved impairments in social behavior and communication in ASD. However, it remains unclear how oxytocin improves such abnormalities. Here, we examined the effects of oxytocin on prenatal VPA-induced ASD-like behaviors.
[Methods] Pregnant ICR (CD1) mice were intraperitoneally administered either VPA 500 mg/kg or saline on E12.5 at a volume of 10 mL/kg body weight. At postnatal day 21, offspring were weaned and sexed, and only male offspring were subjected to this study. Oxytocin 50-200 μg/kg was intranasally administered at a volume of 0.2 mL/kg body weight. Social behavior, recognition memory, and neuronal activity were evaluated by the social interaction test, novel object recognition test, and c-Fos immunohistochemistry, respectively.
[Results] Single intranasal oxytocin administration at 100 and 200 μg/kg, but not at 50 μg/kg, ameliorated prenatal VPA-induced social interaction deficits. Furthermore, this effect lasted for at least 2 h. Immunohistochemical analysis revealed that single administration of oxytocin increased c-Fos-positive cell numbers in the paraventricular nuclei (PVN), prefrontal cortex, and somatosensory cortex, but not the hippocampal CA1 and CA3 regions of VPA-treated mice. In addition, chronic treatments with oxytocin for 2 weeks also ameliorated social interaction deficits in VPA-treated mice without affecting social behavior of control mice, and this effect persisted for at least 24 h. Unlike social behavior, both single and chronic oxytocin administration did not ameliorate the recognition memory impairment.
[Conclusion] These findings suggest that improvement of social interaction deficits is associated with the activation of higher cortical areas and PVN.
