Neurobiology of Astrocytes, Blood-Brain Barrier Transport, and Heavy Metal Neurotoxicology

Michael Aschner
Department of Pediatrics
B-3307 Medical Center North
615-322-8024 (office)

Within the broad area of astrocytic biochemistry and physiology, the laboratory focuses on the role of astrocytes in brain physiology and pathology. Specifically, on-going studies address (1) the mechanisms and consequences of astrocytic swelling, (2) the role of astrocytes in heavy metal (mercury, manganese, and uranium) neurotoxicity, (3) the functional importance of astrocytic metallothioneins in attenuating neurotoxicity, and (4) the responses of astrocytes to chronic exposure to ethanol (EtOH). An important process in the toxic outcome of metals is their transport from plasma into the brain across the capillary endothelial cells that comprise the blood-brain barrier (BBB). In order to cross this barrier, metal complexes must be either highly lipid soluble, or possess affinity for specific carrier-mediated transport systems within the endothelial cell plasma membrane. Little is known about the transport of various metals, and virtually no experimental data exist regarding the transport mechanisms of manganese and uranium across the BBB, a crucial step in the central nervous systems (CNS). Ongoing studies in the lab assess the substrate specificity of manganese and uranium transport into the CNS, testing the hypothesis that the divalent metal cation 1 (DMT1), which has an unusually broad substrate range that includes Fe2+, Zn2+, Mn2+, Co2+, Cd2+, Cu2+, Ni2+ and Pb2+, is mediating their transport into the CNS. The study of these metals is timely, given potential exposure of Gulf War Veterans to depleted uranium, and concern about potential exposure to manganese in the population at large.