Glutamate Neuroexcitotoxicity and Glutathione Depletion
Disturbances in the glutamatergic system are a common feature in autism, with imbalances in both the excitatory and inhibitory networks [92-94]. Glutamate is directly involved in brain development and synaptogenesis, and disrupted glutamatergic signaling is associated not only with autism, but also with epilepsy, schizophrenia, and depression [95]. In one study, children with autism and their family members had elevated levels of glutamate in the blood, along with reduced levels of glutamine [96].
Methylmercury, arsenic, lead, and paraquat exert a common toxic effect by inducing oxidative stress, mitochondrial damage, and depletion of glutathione [8]. The loss of glutathione is mediated in part through the accumulation of extracellular glutamate. Glutamate is the most important excitatory neurotransmitter in the brain, but in excess it becomes neurotoxic. Excessive activation of glutamate receptors leads to excessive calcium influx and activates a cell death cascade due to mitochondrial reactive oxygen species (ROS) [97].
A mechanism that results in glial cells releasing nonvesicular glutamate into the extrasynaptic space is a key factor in pathological glutamate signaling [98]. The cystine-glutamate antiporter system, xc- is the major route by which cysteine is taken up into cells (in its oxidized form as cystine) [97]. Extracellular glutamate is a competitive inhibitor of xc-, preventing uptake of cystine by the cell. Cysteine is the rate-limiting amino acid for glutathione synthesis. Thus, when extracellular glutamate accumulates following toxic exposures, glutathione becomes depleted [79]. N-acetyl cysteine (NAC) has found therapeutic value in treating autism, and this is likely due to the increased bioavailability of cysteine to support glutathione synthesis [99,100].