The animal model of phenylketonuria developed in this laboratory will be used to test hypotheses for the pathogenesis of the mental defect in phenylketonuria. Additional testing will be carried out to provide more complete data on the range of behavioral abnormalities found in animals with experimentally induced phenylketonuria, both during periods of acute hyperphenylalaninemia and after blood phenylalanine concentrations have returned to normal. Counter feeding experiments with other essential amino acids, particularly valine, leucine, and isoleucine will be undertaken to determine if behavioral deficits can be prevented or minimized. The mechanism by which a supplement of valine, leucine, and isoleucine prevents or minimized the anatomic and behavioral deficits associated with high concentrations of phenylalanine in blood and brain will be sought.