Figure 1.

Effect of Mn exposure over the glutamatergic tripartite synapse. (a) Glu/Glu shuttle in normal conditions; Glu levels at the synaptic cleft are tightly regulated by EAATs in glial cells, once inside Glu can be transformed to Gln by GS and then Gln transported by SNATs to the neurons to replenish the Glu stores since Gln can be transformed to Glu by glutaminase. (b) Mn exposure affects the main effector proteins of the Glu/Gln shuttle, when Mn has surpassed the physiological threshold, and Glu tends to accumulate in the synaptic cleft due to the downregulation of EAAT1/2, mostly due to PKC activation. This promotes the overactivation of Glu receptors, even the ones in the extra-synaptic space, triggering the activation of death signaling pathways, a phenomenon known as excitotoxic death. Moreover, GS activity is also diminished along with the downregulation of Gln transporters, distressing all levels of the Glu/Gln cycle rendering defective glutamatergic neurotransmission.