Dai Yu-Chuan, Zhang Hong-Feng, Schön Michael, Böckers Tobias M, Han Song-Ping, Han Ji-Sheng, Zhang Rong
Neuroscience Research Institute, Peking University, Beijing, China.
Key Laboratory for Neuroscience, Ministry of Education, National Health and Family Planning Commission, Peking University, Beijing, China.
Front Cell Neurosci. 2018 Oct 9;12:355. doi: 10.3389/fncel.2018.00355. eCollection 2018.
Autism spectrum disorder (ASD) is characterized by impaired social communication and repetitive/stereotyped behaviors. The neuropeptide oxytocin (OXT) plays a critical role in regulating social behaviors in the central nervous system, as indicated in both human and animal studies. We hypothesized that central OXT deficit is one of causes of etiology of ASD, which may be responsible for the social impairments. To test our hypothesis, central OXT system was examined in valproic acid (VPA)-induced rat model of autism (VPA rat). Our results showed that adolescent VPA rats exhibited a lower level of OXT mRNA and fewer OXT-ir cells in the hypothalamus than control rats. Additionally, OXT concentration in cerebrospinal fluid (CSF) was reduced. The number of OXT-ir cells in the supraoptic nucleus (SON) of neonatal VPA rats was also lower. Autistic-like behaviors were observed in these animals as well. We found that an acute intranasal administration of exogenous OXT restored the social preference of adolescent VPA rats. Additionally, early postnatal OXT treatment had long-term effects ameliorating the social impairments and repetitive behaviors of VPA rats until adolescence. This was accompanied by an increase in OXT-ir cells. Taken together, we demonstrated there was central OXT deficiency in the VPA-induced rat model of autism, and showed evidence that early postnatal OXT treatment had a long-term therapeutic effect on the autistic-like behaviors in VPA rats.
自闭症谱系障碍（ASD）的特征是社交沟通受损以及重复/刻板行为。神经肽催产素（OXT）在调节中枢神经系统的社交行为中起关键作用，这在人类和动物研究中均有表明。我们假设中枢OXT缺乏是ASD病因之一，可能导致社交障碍。为了验证我们的假设，我们在丙戊酸（VPA）诱导的自闭症大鼠模型（VPA大鼠）中检测了中枢OXT系统。我们的结果表明，青春期VPA大鼠下丘脑的OXT mRNA水平低于对照大鼠，且OXT免疫反应阳性细胞数量更少。此外，脑脊液（CSF）中的OXT浓度降低。新生VPA大鼠视上核（SON）中的OXT免疫反应阳性细胞数量也较少。在这些动物中还观察到了类似自闭症的行为。我们发现急性鼻内给予外源性OXT可恢复青春期VPA大鼠的社交偏好。此外，出生后早期给予OXT治疗具有长期效果，可改善VPA大鼠直至青春期的社交障碍和重复行为。这伴随着OXT免疫反应阳性细胞数量的增加。综上所述，我们证明了VPA诱导的自闭症大鼠模型存在中枢OXT缺乏，并表明出生后早期给予OXT治疗对VPA大鼠的类似自闭症行为具有长期治疗效果。
