Copper deficiency during neonatal development alters mouse brain catecholamine levels

Abstract

Copper (Cu) deficiency was investigated in Swiss Webster albino mice to develop a model that alters brain catecholamine metabolism without serious growth impairment. Cu deficiency was induced by feeding a diet low in Cu (modified AIN-76A) to dams beginning either 7 days prior, 4 days prior, 4 days after, or on the day of parturition. Control dams were given Cu in the drinking water (20 μg Cu/mL); their pups were considered Cu-adequate (+Cu). Mice were weaned when three weeks old and were maintained on the treatment of their dams for an additional week. All four-week-old male Cu-deficient (−Cu) offspring exhibited biochemical characteristics of Cu deficiency when compared to their respective +Cu control mice. However, the best model, which resulted in altered catecholamine metabolism characterized by elevation of dopamine (DA) and depression in norepinephrine (NE) in brain and heart, was when treatment began 4 days prior to birth. Body and brain weight were not altered. However, levels of Cu in brain were markedly reduced to 21% of those measured in +Cu controls. Furthermore, brain NE and DA concentrations of −Cu mice were 72% and 132% of those quantified in +Cu offspring, respectively. Confirmatory studies demonstrated equivalent results in female offspring. One-month dietary Cu repletion studies reversed most biochemical changes in the “−Cu” mice. Brain Cu levels remained lower in repleted mice (55% of those in +Cu controls). These data and previous results support the hypothesis that neonatal Cu deficiency results in permanent changes to the brain.