Copper deficiency and the central nervous system. Myelination in the rat: morphological and biochemical studies.

Abstract

Less histologically demonstrable myelin was present in the central nervous system of newborn rats having a mean brain copper concentration only 20% that of normal. Tremor, spontaneous tail elevation and a loss of aggressive character were consistent features. Significant decreases in typical myelin lipids, sulfatide, and especially galactocerebroside were found in agreement with the histological deficit. The composition of gangliosides and phospholipids were unaltered except for a slight enrichment in phosphatidylcholine. Galactosylation of ceramide, in vitro, was depressed in copper-deficient brain and the relevance of this finding is discussed. Swayback, a non-febrile, ataxic disorder of newborn and young lambs, was first reported by Bennetts in Western Australia (4, 5). The disease is associated with low levels of copper in tissue of both ewes and affected lambs (6) due to low copper content in pastures. Supplementation with copper of either the ewe during pregnancy, or the lamb directly, prevents manifestations of the disease (7, 15). Although a well known entity in sheep, a condition resembling swayback also has been reported in copper-deficient goats (26, 37, 41) and pigs (33, 50). The common pathological features of swayback include symmetrical demyelination with subsequent cavitation of the cerebral white matter and degeneration of descending tracts in the spinal cord (28, 42, 43); however, myelin aplasia has also been observed (27). Similar changes have been induced in lambs (31) and guinea pigs (16) born to mothers fed experimental diets deficient in copper, but myelin changes have not been reported in the copper-deficient rat. Demyelination and amyelination accompanying swayback disease in sheep are associated with a depletion of typical myelin lipids such as cerebroside (27). The decrease in lipids may be involved in the pathogenesis of the disease in the nervous system, but the basic defect that results in decreased myelin lipid is not known. Recently, DiPaolo and Newberne (13) observed a variety of clinical and morphological abnormalities in copper-deficient newborn rats which include a high mortality, retarded growth, petechial and ecchymotic hemorrhages in brain, muscle and subcutaneous tissue, focal necrosis in the brain associated with neonatal incoordination of the hind limbs, hemorrhagic necrosis of the liver, cardiac hemorrhage, and severe, widespread vascular dilation in cardiac walls and septae. We also observed behavioral changes in rats having a mean brain copper concentration about 20% of normal. The purpose of this report is to describe further these changes, present the histological myelin anomalies observed in these animals, and correlate this morphological observation with quantitation of brain lipids and the in vitro synthesis of galactocerebroside.