Autism is a neuro-developmental disorder. This program will make use of new discoveries to bring research on autism into the context of modern developmental biology, neurobiology, and molecular genetics. 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 case of autism resemble features of the Hoxa-1 transgenic knockout mouse. This suggests 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 functional 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. Animal Models of Autism and Mechanisms of Injury, we shall compare the effects of valproic acid, hexanoic acid and retinoic acid on the Hox gene cascade, using mice transgenic for lacZ markers of Hoxa-1 expression, in situ hybridization for markers of the rhombomeres, and staining for neurofibrils. We shall develop animal models transgenic for human mutations involved in autism. Finally, we shall test for interactions between early developmental gene mutations and teratologic exposure. The goal is to understand how teratologic agents and genetic anomalies produce similar effects on the hindbrain. Project II. Behaviors Discriminating Autism in Humans and Animals, is an investigation of two behavioral tasks with promise to discriminate autism from other developmental disabilities. Both the conditioned eye-blink response and an attention task have already been shown to be affected in autism. The long- term goal is to develop animal tasks that can serve as markers of the injury that causes autism so that animal models can be tested for parallelism to the human disorder. Project III. Genotype and Phenotype in Autism and Behaviorally-Related Disorders, will assess behavioral symptomatology, minor physical anomalies, and neurological/ophthalmological deficits, and mutations of early developmental genes in four developmentally disabled groups (autism, Asperger syndrome, Moebius syndrome, and semantic-pragmatic language disorder) and normal controls. The goal is to determine whether the phenotypic or genotypic features of these disorders indicate a common etiology.
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