Figure 4. MeHg-induced glutamate and calcium dyshomeostasis and oxidative stress.

MeHg causes increased extracellular glutamate (GLU) levels via the inhibition of astrocytic glutamateuptake (event 1) and the stimulation of glutamate release from pre-synaptic terminals (event 2). Increased extracellular glutamate levels overactivate N-methyl D-aspartate (NMDA)-type glutamate receptors, increasing calcium influx into neurons (event 3). Increased levels of intracellular calcium, which can lead to mitochondrial collapse (event 4), activate neuronal nitric oxide synthase (nNOS) (event 5), thus increasing nitric oxide (NO) formation. MeHg affects the mitochondrial electron transfer chain (mainly at the level of complexes II–III) (event 6), leading to increased formation of reactive oxygen species [ROS; superoxide anion (O₂^•−) and hydrogen peroxide (H₂O₂)]. H₂O₂ can inhibit astrocyte glutamate transporters (event 7), contributing to the excitotoxic cycle. O₂^•− reacts with NO (event 8), generating peroxynitrite (ONOO^•), a highly oxidative molecule. Adapted from Farina et al., 2011a.