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Nutritional Neurosciences

Neurological Dysfunction Occurs in Mice with Targeted Deletion of the Selenoprotein P Gene^1,2

Division of Gastroenterology and Clinical Nutrition Research Unit, Vanderbilt University School of Medicine, Nashville, TN 37232 and ^* Eccles Institute of Human Genetics, The University of Utah, Salt Lake City, UT 84112

³To whom correspondence should be addressed. E-mail: raymond.burk{at}vanderbilt.edu.

Brain function and selenium concentration are well maintained in rodents under conditions of selenium deficiency. Recently, however, targeted deletion of the selenoprotein P gene (Sepp) has been associated with a decrease in brain selenium concentration and with neurological dysfunction. Studies were conducted with Sepp^-/- and Sepp^+/+ mice to characterize the neurological dysfunction and to correlate it with dietary selenium level. When weanling Sepp^-/- mice were fed the basal diet (<0.01 mg/kg selenium) supplemented with 0, 0.05 or 0.10 mg selenium/kg, they developed spasticity that progressed and required euthanasia. Supplementing the diet with 0.25 mg selenium/kg prevented the neurological dysfunction. To determine whether neurological dysfunction would occur in more mature Sepp^-/- mice deprived of selenium, Sepp^-/- mice that had been fed the basal diet supplemented with 1.0 mg selenium/kg for 4 wk were switched to a selenium-deficient diet. Within 3 wk they had developed neurological dysfunction and weight loss. At 3 wk, the 1.0 mg selenium/kg diet was reinstituted. Neurological function stabilized but did not return to normal. Brain selenium concentration did not increase. Weight gain resumed. This study shows that neurological dysfunction occurs when selenium supply to the brain is curtailed and that the dysfunction is not readily reversible. Both the absence of selenoprotein P and a low dietary selenium supply are necessary for the dysfunction to occur, indicating that selenoprotein P and at least one other form of selenium supply the element to the brain.

KEY WORDS: • deletion of selenoprotein P • mouse selenoprotein P • neurological dysfunction • selenium transport to brain

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