The clear link between neonatal hyperphenylalaninemia and severe, irreversible cognitive impairment offers a unique opportunity to study the role(s) played by several biochemical processes in the development of brain structure and ultimate cognitive functioning. The proposed research is designed the examine the lasting cognitive effects of three biochemical disturbances that result from HP: (1) brain protein synthesis inhibition, (2) inhibition of brain catecholamine synthesis, and (3) suppression of brain serotonin synthesis. Since each of these disrupted metabolic processes seems to play a critical role(s) in neural ontogeny, their disruption during early development may permanently affect brain function. Two approaches will be used to provide converging information on the effects of each, (1) these three metabolic abnormalities will each be pharmacologically induced during the suckling period; and (2) each of these disturbances will be independently prevented in HP rat pups. Biochemical, behavioral, and neuroanatomical measurements will all be taken, thus providing the optimal circumstances for integrating these different domains. In addition to its implications for basic science, the results of this research should have significant applied value. First, a knowledge of the functional consequences of developmental monoamine deficiencies is critical for determining the fetal risk that is incurred when pregnant and/or lactating women take drugs that have such effects. Second, determining the pathogenesis of HP-induced cognitive dysfunction is critical for improving the treatment of phenylketonuria, a genetic disease that produces both HP and permanent mental retardation.
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