Creatine (Cr) is an essential component of cellular energy storage and production in tissues with high energy requirements. Creatine deficiency in humans is caused by a small group of rare inborn errors of metabolism involving synthesis and transport. In contrast, creatine supplementation is purported to have a protective effect on neurologic progression in disease models of amyotrophic lateral sclerosis, Huntington's disease, and Parkinson's disease. Furthermore, prophylactic creatine administration in animals appears to be neuroprotective in models of traumatic and ischemic brain injuries. ? ? The most significant utilization of creatine occurs in muscle and brain. In these organs, creatine and phosphocreatine, together with creatine kinase isozymes and ATP/ADP, provide the major reserve of energy. Deficiency of the first enzyme in the creatine synthetic pathway, arginine:glycine amidinotransferase (AGAT), in humans leads to complete deficiency of creatine synthesis and severe neurological sequelae, including mental retardation and autistic features. However, newborns appear normal and early treatment may eliminate neurologic injury. Thus, creatine deficiency appears to be an excellent candidate for newborn screening. ? ? Using a mouse model of AGAT deficiency, the goal of this application is to provide insights into the pathologic mechanisms of this inherited metabolic disease with regard to learning and synaptic plasticity. The investigators will use behavioral testing in conjunction with electrophysiology to examine the neurologic phenotype and its response to creatine supplementation. They are also interested in understanding the effect of creatine deficiency on muscle bioenergetics using various physiologic and biochemical assays, including exercise testing, tissue and fluid analytes, magnetic resonance spectroscopy, and mitochondrial respiration with skinned muscle fibers. Also to be investigated are the effects of oral creatine administration as a neuroprotective agent by determining the threshold for seizure induction and sensitivity to hypoxic injury. These studies will provide insights into a screenable human disorder as well as broader biomedical issues. ? ? ? ?
