This Program Project is focused on identification of the most critical period for defective development of the brain in autistic children and of mechanisms that cause the dramatic delay of growth of neurons during the first several years of life in children with autism. Our preliminary studies revealed that in 4- to 7-year-old children with autism, neurons in the nucleus accumbens (human "social brain") show the most dramatic delay of growth. This may explain the lack of attachment and the social isolation of the autistic child. Severe developmental delay of neurons in the amygdala may correspond to cognitive deficits, aggression, and self-abuse, as well as anxiety. Significant underdevelopment of neurons in the caudate nucleus and putamen appears to contribute to ritualistic behaviors and stereotypes. The proposed project will determine the type and severity of developmental changes in 2- to 7-year-old children with autism and the mechanisms interfering with stimulation of the normal growth of neurons and development of functional networks. The success of this research may result in treatments that partially or entirely restore levels of growth factors and prevent structural and functional deterioration of the child brain if applied in the early phase of the disease. The regressive type of autism, with normal or almost normal development at the age of 1.5 years, and sudden deterioration, might be a potential target of this type of therapeutic approach. The role of the hypothalamus in developmental deficits: Detection of deficits of the hypothalamic neuroendocrine system with reduced levels of oxytocine, vasopressin, brain-derived growth factor, and neurotrophins may result in application of biologically active supplements during early childhood. Numerous markers of structural correction of brain size, volume of neurons, and possibly neuronal connectivity observed in late childhood suggest that treatments in the critical period of brain development may prevent life-long disabilities. This 3-year project will identify the pattern of pathological changes, elucidate the contribution of the hypothalamic neuroendocrine system to early childhood abnormal brain growth, and determine targets for treatments. Sudden death of autistic subjects with chromosome 15 duplication: In this project, we will examine the brains of 22 people with autism with unknown cause of disease and of 12 people diagnosed with isodicentric chromosome 15 (idic15) and autism. This will be the largest cohort to be examined postmortem and the first study of brains of people with idic15. The very high mortality of children and adults with idic15 (1.5% per year) requires identification of cases of sudden unexpected death. One of the main aims of this project is to establish whether sudden death is caused by brain pathology. Comparative study of brains of people with unknown cause of disease and with genetically determined cause of autism (idic15) may result in criteria for subclassification of autism according to clinical, neuropathological, and biochemical criteria.