Manganese neurotoxicity and glutamate-GABA interaction

Brain extracellular concentrations of amino acids (e.g. aspartate, glutamate, taurine) and divalent metals (e.g. zinc, copper, manganese) are primarily regulated by astrocytes. Adequate glutamate homeostasis is essential for the normal functioning of the central nervous system (CNS). Glutamate is of central importance for nitrogen metabolism and, along with aspartate, is the primary mediator of the excitatory pathways in the brain. Similarly, the maintenance of proper manganese levels is important for normal brain functioning. Several in vivo and in vitro studies have linked increased manganese concentrations with alterations in the content and metabolism of neurotransmitters, namely dopamine, gamma-aminobutyric acid, and glutamate. It has been reported by our laboratory and others, that cultured rat primary astrocytes exposed to manganese displayed decreased glutamate uptake, thereby increasing the excitotoxic potential of glutamate. Furthermore, decreased uptake of glutamate has been associated with decreased gene expression of glutamate:aspartate transporter (GLAST) in manganese-exposed astroctyes. Additional studies have suggested that attenuation of astrocytic glutamate uptake by manganese may be a consequence of reactive oxygen species (ROS) generation. Collectively, these data suggest that excitotoxicity may occur due to manganese-induced altered glutamate metabolism, representing a proximate mechanism for manganese-induced neurotoxicity.