Autism model rat by maternal thalidomide/valproic acid exposure : Implication for pathogenesis of autism

自闭症通常被理解为一种异质性疾病，受到复杂因素的影响，包括遗传因素、环境因素和改变胎儿神经发育的致畸因素。我们最近建立并报告了一种自闭症模型大鼠，通过将早期大鼠胚胎暴露于沙利度胺(Thal)或丙戊酸(VPA)，这两种已知的自闭症诱发畸形物(Narita，et al.，Pediatrics Research，2002)。为了简化模型大鼠的病理，我们特别关注模型大鼠中的一种神经递质5-羟色胺，因为大多数自闭症症状可以用5-羟色胺能功能障碍来解释。到目前为止，我们已经发现大脑和血液中的血清素浓度增加。尤其重要的是调查Thal/VPA暴露的大鼠的行为特征，以评估它们是否表现出与人类自闭症的相似性。因此，我们检验了(1)Morris水迷宫试验、(2)八环径向迷宫试验和(3)开野试验，这些试验是大鼠行为学研究中常用的方法。水迷宫实验未见明显改变。在径向迷宫实验中，沙利度胺组和VPA组的学习任务成绩受损(分别为40%，60%，VPA组为75%)。有趣的是，与对照组相比，模型组大鼠出现非探索性运动(无目的的跑步和行走)的频率更高，这让人想起了人类自闭症。在旷场测试中，模型大鼠的自发活动仅在连续三天的第一次会议中与对照组相比增加(经双因素方差分析，P&lt；0.01，数据未显示)。总而言之，暴露于E9Thal和VPA的大鼠被认为与5-羟色胺和行为发育有共同的病因学，这与人类自闭症患者密切相关。

Autism is generally understood as a heterogeneic disease, affected by complex factors including genetic factors, environmental factors, and teratogens that alter fetal neurological development. We have recently established and reported an autism model rat, by exposing early-stage rat embryo to either thalidomide (THAL) or valproic acid (VPA), the two known autism-inducible teratogens (Narita, et al., Pediatrics research, 2002). To simplify the pathology of the model rats, we have particularly focused on a neurotransmitter serotonin in the model rats, because most of the autistic symptoms can be explained by serotonergic dysfunction. To date, we have found increased serotonin concentration in the brain and blood. It is particularly important to investigate behavioral features of THAL/VPA-exposed rats to asses whether they exhibit any similarity to human autism. Thus, we have examined (1)Morris water maze test, (2)eight-arrn radial maze test, and (3)open field test, that are commonly used for the rat behavioral studies. No significant changes were found in the water maze test. In the radial maze test, impairment of the learning task achievement was observed in the thalidomide and VPA groups compared to the control group (40%, 60%, vs 75%, respectively). Interestingly, non-exploratory movement (purposeless running and walking) was more frequently seen in the model rats compared to the controls, which is a reminiscence of human autism. In the open field test, spontaneous activity was increased in the model rats compared to the controls only in the first session of the successive three days session (p<0.01 in THAL vs control, by two-way ANOVA, data not shown). In summary, the E9 THAL-and VPA-exposed rats are supposed to have common etiology regarding serotonin and behavioral development, which are closely related to human autistic patients.