Identification of the embryonic stage when injury can cause autism has led to the insight that the disorder is initiated by changes in the developing brain stem. The shortening of the hindbrain and loss of cranial nerve neurons in an animal model of the insult and a human cause of autism resemble features of the Hoxa-1 transgenic knockout mice. Thus, it is now possible to suggest a unifying hypothesis regarding the multiple etiologies of autism; We propose that teratogens and genetic defects lead to similar developmental changes in the brain stem because mutations of early developmental genes are the cause of familial cases and the teratogens which cause the disease act by interfering with the function of the same genes. The new finding that one of the candidate genes is abnormal in some cases of autism supports this hypothesis. In Project I. we shall create an animal model based on mutation of early developmental genes. We have already developed an animal model based on mutation of early developmental genes. We have already developed an animal model of teratologically-induced brain stem injury using valproic acid. Our plan to evaluate the behavior of animal models await the identification of tasks which a) discriminate autism from other developmental disabilities b) are applicable to animals c) are restricted in the functions required so that they might be connected to specific brain regions or systems. We have identified two tasks with the potential to meet these criteria- the conditioned eye-blink response in teratologic and genetic animal models of autism, and then apply the same task to human cases of autism and other developmental disabilities. A long-term goal is to develop an animal analogue of the attention task which will be applied to teratologic and genetic animal models of autism. The overall goal of this project is to provide tests of behavioral parallelism not only in our own animal models of autism, but in those developed by others.
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