Chapter 11: Impairment of Glutamine/Glutamate-γ-aminobutyric Acid Cycle in Manganese Toxicity in the Central Nervous System

Glutamine (Gln) is abundantly expressed in the central nervous system (CNS), where it participates in a variety of metabolic pathways. In the mammalian brain, Gln functions via complex glutamine/glutamate-γ-aminobutyric acid cycle (GGC), where Gln efflux from astrocytes must be met by its influx in neurons. Manganese (Mn) toxicity is associated with the disruption of both of these critical points in the GGC, leading to the changes in Glu-ergic or GABA-ergic neurotransmission. Proper astrocyte function is imperative for glutamatergic/GABA metabolic clearance and recycling. In vivo and in vitro studies showed that Mn evokes mitochondrial abnormalities, oxidative/nitrosative stress, and morphological/functional changes of astrocytes, a major player in GGC cycling. Overdose and excessive Mn accumulations in astrocytes not only culminate in pathology, but also affect astrocytic protective properties and defect or alternate astrocyte–neuronal integrity. In this chapter, we highlight the mechanistic commonalities inherent to Mn neurotoxicity related to the astrocyte pathology and GGC impairment.