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].