Rationale: Rodents exposed to valproic acid (VPA) in prenatal life exhibit post-natal characteristics analogous to autism spectrum disorder (ASD). Many previous studies used relatively high doses of VPA during early pregnancy, potentially confounding interpretation because the offspring are the 'survivors' of a toxic insult. Low dose or late gestation exposure has not been widely studied. Objectives: We examined the behavioral sequelae of late gestation exposure to low dose VPA in the mouse. We also examined postnatal levels of glutamic acid decarboxylase (GAD65 and GAD67) as markers for GABA neurons, because GABA pathology and subsequent excitatory/inhibitory imbalance is strongly implicated in ASD. Methods: Pregnant C57BL/6N mice received a single subcutaneous injection of 100 or 200 mg/kg on gestation day 17. The control group received a saline injection on the same day. The offspring were tested in a battery of behavioral tests in adolescence and adulthood. Six brain regions were harvested and GAD65 and GAD67 were measured by western blotting. Results: Compared to saline-exposed controls, adult mice exposed to prenatal VPA had impaired novel object exploration and fear conditioning anomalies. GAD67 was decreased in midbrain, olfactory bulb, prefrontal cortex and increased in cerebellum, hippocampus and striatum; GAD65 was decreased in all 6 regions. Conclusions: Our results suggest that a low dose of VPA in late pregnancy has persistent effects on brain development, and in particular the GABA system, which may be relevant to ASD. Further attention to the impact of gestation time and dose of exposure in VPA-induced ASD models is encouraged. (C) 2016 Published by Elsevier B.V.
基金:
University of Hong Kong; Medicine and Health Science Technology Development Plan of Shandong Province [2014WS0315]; Sackler Institute for Translational Neurodevelopment at King's College London; MRC [MR/N026063/1] Funding Source: UKRI; Medical Research Council [MR/N026063/1] Funding Source: researchfish
第一作者单位:[1]Shandong Acad Med Sci, Inst Basic Med, Jingshi Rd 18877, Jinan 250062, Shandong, Peoples R China[2]Univ Hong Kong, Dept Psychiat, Pokfulam, Hong Kong, Peoples R China
通讯作者:
通讯机构:[1]Shandong Acad Med Sci, Inst Basic Med, Jingshi Rd 18877, Jinan 250062, Shandong, Peoples R China[2]Univ Hong Kong, Dept Psychiat, Pokfulam, Hong Kong, Peoples R China
推荐引用方式(GB/T 7714):
Wei Ran,Li Qi,Lam Sylvia,et al.A single low dose of valproic acid in late prenatal life alters postnatal behavior and glutamic acid decarboxylase levels in the mouse[J].BEHAVIOURAL BRAIN RESEARCH.2016,314:190-198.doi:10.1016/j.bbr.2016.08.006.
APA:
Wei, Ran,Li, Qi,Lam, Sylvia,Leung, Jana,Cheung, Charlton...&McAlonan, Grainne Mary.(2016).A single low dose of valproic acid in late prenatal life alters postnatal behavior and glutamic acid decarboxylase levels in the mouse.BEHAVIOURAL BRAIN RESEARCH,314,
MLA:
Wei, Ran,et al."A single low dose of valproic acid in late prenatal life alters postnatal behavior and glutamic acid decarboxylase levels in the mouse".BEHAVIOURAL BRAIN RESEARCH 314.(2016):190-198