摘要
目的比较丙戊酸(VPA)诱导的C57小鼠和SD大鼠孤独症谱系障碍(ASD)模型在生理发育、神经发育和孤独症样行为等方面的异同,为合理选择ASD动物模型提供实验依据。方法孕12.5 d的C57小鼠和SD大鼠,分别ip给予VPA 600 mg·kg^-1或无菌生理盐水(正常对照组)。观察各组孕鼠出产率;新生仔鼠的外观畸形率;雄性仔鼠的4日存活率、体质量、尾长和尾部外观畸形率,以及腹毛生长、门齿萌出和睁眼时间等生理发育指标;雄性仔鼠的平面翻正反射、空中翻正反射、转体、断崖回避反射、直线爬行、抓杆和听觉惊愕反射行为达到阳性的天数等神经发育指标;并通过旷场实验、三箱社交实验和自我捋毛实验检测各组雄性仔鼠的孤独症样行为。结果与各自正常对照组相比,C57小鼠VPA组孕鼠出产率明显降低(P<0.05),新生仔鼠外观畸形率显著升高(P<0.01),而SD大鼠VPA组孕鼠出产率和新生仔鼠外观畸形率均无差异。C57小鼠VPA组雄性仔鼠较其正常对照组的4 d存活率降低(P<0.05)、在出生后20和25 d时体质量较轻(P<0.05)、门齿萌出和睁眼时间延迟(P<0.05,P<0.01);SD大鼠VPA组雄性仔鼠在相同日龄时体质量虽也明显低于其正常对照组(P<0.01),但4 d存活率、腹毛生长、门齿萌出时间和睁眼时间无差异。C57小鼠VPA组雄性仔鼠的转体和抓杆实验达阳性天数明显滞后(P<0.05),但在平面翻正、断崖回避、空中翻正、直线爬行和抓杆实验中无明显差异;SD大鼠VPA组雄性仔鼠的平面翻正(P<0.01)、断崖回避(P<0.01)、空中翻正(P<0.05)、直线爬行(P<0.01)和抓杆实验(P<0.01)达阳性天数均有显著延迟,但在转体实验中无明显差异。在三箱社交实验、旷场实验和自我捋毛实验中,C57小鼠VPA组雄性仔鼠空间探索力和对新鲜事物偏好降低(P<0.05);SD大鼠VPA组雄性仔鼠不仅出现明显的空间探索力下降(P<0.01),还伴有明显的社交缺陷(P<0.01)、缺乏社交偏好和新鲜事物偏好(P<0.01)和重复刻板行为(P<0.05)。结论孕中期注射VPA的C57小鼠和SD大鼠,其子代雄性仔鼠均可出现典型的孤独症谱系障碍核心症状,但在母鼠孕产情况、建模成本和模型表观效度等方面,SD大鼠较C57小鼠更适于制备ASD动物模型。
OBJECTIVE To compare the difference and similaritiy in growth, neurodevelopment and neurobehavioral characteristics between SD rat and C57 mouse models of valproic acid (VPA)-induced autism spectrum disorder (ASD), and select an appropriate experimental species for the study of ASD. METHODS SD rats or C57 mice were ip given VPA 600 mg·kg^-1 on embryonic day 12.5 of gestation (VPA groups) or an equal dosage of saline (normal control group). The farrowing rate of pregnant rats or mice and 4-day survival rate were observed. The male pups′ malformation rate, body mass, tail length, incisor eruption, eye opening and development of fur were detected to observe physiological development. The neurodevelopment was measured in male pups including the number of days taken by surfacing righting reflex, cliff avoidance reflex, air righting reflex, pivoting, crawling and bar holding test and auditory startle to become positive. In addition, three chamber sociability test, open-field test and self-grooming test were used to assess autistic-like behaviors. RESULTS Compared with C57 mice in normal control group, the VPA groups presented a low farrowing rate in pregnant mice (P<0.05), and high external abnormality in new born offspring (P<0.01). However, there was no significant difference between SD rats in normal control group and those in VPA group. Compared with C57 mice in normal control group, the 4-day survival rate of offspring of the VPA group was significantly reduced (P<0.05), but there was no significant difference between SD rats in normal control group and those in VPA group. The male offspring of C57 mice in VPA group showed significant growth retardation compared with the normal control group, such as lower body mass at 20 and 25 d after birth (P<0.05), delayed incisor eruption (P<0.05) and eye opening (P<0.01). Although the body mass of the male offspring SD rats in VPA group was also significantly lower than that of normal control group at the same time points (P<0.01), there was no significant delay in the incisor eruption or eye opening. Compared with the male offspring of SD rats in normal control group, the VPA group had a significant delay in surface righting reflex (P<0.01), cliff avoidance reflex (P<0.01), air righting reflex (P<0.05), crawling (P<0.01) and bar holding test (P<0.01). Compared with the normal control group, pivoting (P<0.05) and bar holding test (P<0.05) in the C57 mice VPA group were delayed. In the three chamber sociability test, open field test and self-grooming test, the male offspring of SD rats in VPA group showed decreased spatial exploration ability (P<0.01), impaired social preference and novelty preference (P<0.01), and repetitive and stereotyped behaviors (P<0.05). VPA mice only exhibited reductions in spatial exploration ability and novelty preference (P<0.05). CONCLUSION If SD rats and C57 mice are exposed to VPA in the second trimester of pregnancy, their male offspring exhibits behavioral abnormalities relevant to ASD. However, SD rats are superior to C57 mice in building ASD animal models in terms of maternal pregnancy condition, cost and model face validity.
作者
胡宇玲
郑文霞
侯倩伶
汪小青
陈思思
徐梦洲
茹思兰江·安外尔
陈笛
HU Yu-ling;ZHENG Wen-xia;HOU Qian-ling;WANG Xiao-qing;CHEN Si-si;XU Meng-zhou;Ru-si-lan-jiang·AN WAI-ER;CHEN Di(Institute of Neuroscience, Basic Medical College, Chongqing Medical University, Chongqing 400016, China)
出处
《中国药理学与毒理学杂志》
CAS
北大核心
2019年第3期184-192,共9页
Chinese Journal of Pharmacology and Toxicology
基金
重庆市渝中区科学技术委员会基础科学与前沿技术研究项目(20160112)~~
