Recent studies have suggested that the globus pallidus may be a particularly sensitive target of manganese (Mn), however, in vitro studies of the effects of Mn on GABAergic neurons have been restricted by the lack of a cell model expressing GABAergic properties. Here we investigated the effects of low-level Mn treatment on cellular GABA and glutamate metabolism using the newly characterized AF5 rat neural-derived cell line, which displays GABAergic properties during culture in vitro. Intracellular GABA and glutamate levels were measured along with measurement of the release of GABA and glutamate into the culture medium, glutamine uptake from the culture medium, and the specific effects of Mn on the enzymes directly responsible for the synthesis and degradation of GABA, glutamate decarboxylase (GAD) and GABA transaminase (GABA-T). Our results demonstrate that Mn had no effect on the activities of GAD or GABA-T. Similarly, low-level Mn treatment of AF5 cultures had only a small effect on intracellular GABA levels (114% of control) and no effect on the release of GABA. In contrast, intracellular and extracellular glutamate levels were enhanced to 170% and 198% of control during Mn treatment, respectively, while extracellular glutamine decreased to 73% of controls. Together, these results suggest that glutamate homeostasis may be preferentially affected over GABA in AF5 cells during low-level Mn treatment, suggesting a novel mechanism by which Mn-induced excitotoxicity might arise.
Analyses of brains from six infants whose birth weights were "small for gestational age" (SGA) and ten infants whose birth weights were ‘appropriate for gestational age" (AGA) show the cerebellum to be the area of the brain most greatly affected by intrauterine underdevelopment. The SGA cerebellar weight was reduced 37% and cellularity 35%, compared to reductions of only 21% and 19% for weight and cellularity in the remainder of the brain. The myelin lipids, cerebroside and sulfatide, were significantly reduced (p < .01) in concentration or total quantity in the brains of SGA infants, in contrast to phospholipids, cholesterol, and gangliosides which did not show a similar reduction. Galactolipid sulfotransferase activity, important in sulfatide formation, was also significantly reduced (p < .01) in the brains from SGA infants.
The guinea pig, like the human, initiates the period of rapid brain growth in utero and thus provides a model for measuring the effects of maternal malnutrition on intra-uterine brain growth. In these studies the newborn of undernourished guinea pig mothers showed significant reductions in body weight and brain weight, cellularity, protein, cholesterol, cerebroside, and sulfatide contents. The reductions in wet brain weight and protein content were significant for cerebellum but not for cerebrum. Animals undernourished in utero and fed normally after birth showed normal whole brain weight, cerebroside and sulfatide contents, and normal cerebrum cellularity by adulthood. However, the type of cells increasing in the cerebrum during postnatal rehabilitation is unknown. Wet weight and cellularity were still diminished by 22% and 17%, respectively, in the adult cerebella. The results suggest that adequate postnatal nutrition will offset some, though not all of the brain biochemical changes resulting from fetal undernutrition.
Offspring brain lipid development has been studied following the amino acid fortification of wheat diet fed to pregnant and lactating rats. Comparisons are made with a 13% casein diet which contains a similar quantity of protein of known high quality, with a 26% casein diet, and with a standard laboratory diet. Increased maternal energy intake was found, particularly during lactation, with protein quality improvement. Offspring of mothers receiving the unsupplemented bread diet had lower total brain cholesterol, phospholipid, cerebroside-sulfatide, and (for 4 of the 5 other diets) ganglioside-NANA levels in comparison to offspring whose mothers received the other diets. Brain cerebrosidesulfatide and cholesterol concentrations were also lower in the offspring whose mothers received the unsupplemented bread, suggesting impaired myelin formation. Phospholipid and ganglioside-NANA concentrations were not lower. Fortification of the bread diet with lysine resulted in increases in both the total levels and concentrations of cerebroside-sulfatide and cholesterol. When both lysine and threonine were added, the cerebroside-sulfatide and cholesterol levels and concentrations were similar to or greater than values for the two casein diets and the standard laboratory diet. The 2600 casein diet did not result in higher lipid values than obtained with the 13% casein diet. This study demonstrates the adequacy of amino acid supplementation of a maternal cereal protein diet in allowing normal offspring brain lipid development.
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