Oxytocin attenuates deficits in social interaction but not recognition memory in a prenatal valproic acid-induced mouse model of autism
Introduction
Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by core symptoms including impairments in social behavior and communication (Geschwind and Levitt, 2007, Persico and Bourgeron, 2006). Individuals with ASD often also display other symptoms, such as cognitive impairment, hyperactivity, anxiety, and sensory abnormalities (Cervantes and Matson, 2015, Gadke et al., 2016, Joshi et al., 2010, Yeargin-Allsopp et al., 2003).
Although the etiology of ASD remains elusive, clinical research has indicated that doses of valproic acid (VPA) during pregnancy increases the incidence of autism in children (Christensen et al., 2013, Ornoy, 2009). We recently reported that prenatal VPA exposure at embryonic day 12.5 (E12.5) induces ASD-like behavioral abnormalities, including social interaction and recognition memory impairments, in male mice (Kataoka et al., 2013). Furthermore, we suggest that the brain regions responsible for social and recognition memory impairments are the cortical areas and hippocampus, respectively (Takuma et al., 2014).
Oxytocin, a neuropeptide synthesized in the paraventricular nucleus (PVN) and supraoptic nucleus of the hypothalamus (Lee et al., 2009), is known to play a critical role in a range of social behaviors, such as maternal behavior, pair bonding, sexual behavior, and social memory/recognition (Insel, 2010, Ross and Young, 2009). It has been suggested that alterations in the oxytocinergic system are associated with the pathogenesis of ASD. Genetic studies revealed that single nucleotide polymorphisms in the oxytocin receptor were a risk factor for ASD (Lerer et al., 2008, Liu et al., 2010, Wu et al., 2005). In animal studies, both oxytocin knockout mice (Lazzari et al., 2013, Winslow et al., 2000) and oxytocin receptor knockout mice (Pobbe et al., 2012a, Pobbe et al., 2012b, Sala et al., 2011, Takayanagi et al., 2005) display ASD-like behavioral abnormalities. Accordingly, recent animal studies reported that intraperitoneally (Peñagarikano et al., 2015, Teng et al., 2013, Teng et al., 2016) or subcutaneously (Meziane et al., 2015) administered oxytocin attenuated social behavioral deficits in animal models of ASD. Furthermore, recent clinical studies also showed that intranasal treatment with oxytocin improved impairments in socio-communication and social reciprocity in people with ASD (Watanabe et al., 2014, Watanabe et al., 2015). However, it remains unclear how oxytocin exerts these ameliorating effects on ASD-like behaviors, especially when administered intranasally.
In the present study, we examined the effects of intranasal oxytocin on social interaction deficits and recognition memory impairments in mice exposed prenatally to VPA. Furthermore, we analyzed c-Fos expression in the brain of oxytocin-treated ASD mice. In addition, we investigated the effect of repeated treatment with intranasal oxytocin.
Section snippets
Animals
ICR (CD1) mice were purchased from Japan SLC Inc. (Hamamatsu, Japan) at 8 weeks of age. The mice were housed individually in plastic cages (28 × 17 × 12 cm) under a standard light/dark cycle (12-h light cycle starting at 8:00) at a constant temperature of 22 ± 1 °C. The animals had ad libitum access to food and water, and were handled in accordance with the guidelines established by the Animal Care and Use Committee of the Graduate Schools of Pharmaceutical Sciences and Dentistry, Osaka University, the
Effects of a single administration of oxytocin on social interaction deficits in mice prenatally exposed to VPA
We examined the dose-dependent effects of a single administration of oxytocin on prenatal VPA-induced social interaction deficits (Fig. 1). Two-way ANOVA showed significant main effects of oxytocin administration (F3,85 = 5.79, P < 0.01, η2 = 0.108) and prenatal VPA exposure (F1,85 = 15.18, P < 0.001, η2 = 0.094), and a significant interaction between both effects (F3,85 = 15.52, P < 0.0001, η2 = 0.289). Post-hoc Tukey's multiple comparison tests revealed that intranasal administration of oxytocin over 100 μg/kg
Discussion
There is no drug approved to treat social behavioral impairments in people with ASD. Much attention has recently been paid to oxytocin because of its effectiveness in improving social behavioral deficits in people with ASD (Watanabe et al., 2014, Watanabe et al., 2015). Recent animal studies have also suggested a potentially useful role of oxytocin in ASD therapy. Meziane et al. (2015) demonstrated that subcutaneous treatment with oxytocin in the first weeks of life prevented social and
Conclusions
A single intranasal administration of oxytocin improved social interaction deficits, but not recognition memory impairment, in VPA-exposed mice. A single intranasal administration of oxytocin in VPA-exposed mice also increased c-Fos expression in the PVN, PFC, and SsCx, but not the hippocampal CA1 and CA3 regions. These findings suggest that oxytocin attenuates social interaction deficits through the activation of higher cortical areas in VPA-exposed ASD model mice. The present study further
Funding
This study was supported in part by JSPS KAKENHI [JP13J05359 (YH), JP25460099 (YA), JP16K08268 (YA), JP26293020 (HH), JP26670122 (HH), JP15H01288 (HH), 17H03989 (HH) and JP16K15126 (KT)], the Neuropsychiatry Drug Discovery Consortium established by Dainippon Sumitomo Pharma Co., Ltd. (Japan) with Osaka University (TM, HH), Dainippon Sumitomo Pharma Joint Research Fund (KT), Uehara Memorial Foundation (Japan) (KT), Research Foundation for Pharmaceutical Sciences (Japan) (YA), the JSPS Program
Conflict of interest
The authors declare that they have no conflict of interest.
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