Manganese toxicity in the central nervous system: the glutamine/glutamate‐γ‐aminobutyric acid cycle

Manganese ( M n) is an essential trace element that is required for maintaining proper function and regulation of numerous biochemical and cellular reactions. Despite its essentiality, at excessive levels M n is toxic to the central nervous system ( CNS ). Increased accumulation of M n in specific brain regions, such as the substantia nigra, globus pallidus and striatum, triggers neurotoxicity resulting in a neurological brain disorder, termed manganism. M n has been also implicated in the pathophysiology of several other neurodegenerative diseases. Its toxicity is associated with disruption of the glutamine ( G ln)/glutamate ( G lu)‐γ‐aminobutyric acid ( GABA ) cycle ( GGC ) between astrocytes and neurons, thus leading to changes in G lu‐ergic and/or GABA ergic transmission and G ln metabolism. Here we discuss the common mechanisms underlying M n‐induced neurotoxicity and their relationship to CNS pathology and GGC impairment.