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

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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.