EAATs mediate rapid uptake of glutamate from the synaptic cleft. This is required to keep glutamate concentrations in the synaptic cleft very low.
Prolonged activation of inotropic glutamate receptors causes increased influx of calcium and sodium into postsynaptic neurons. This activates an intracellular cascade resulting in mitochondrial dysfunction and increased formation of reactive oxygen (ROS) and nitrogen species (RNS) such as superoxide anion, NO and peroxynitrite and, subsequently, cell death. Neuronal cell damage induced by over-excitation of AMPA or NMDA receptors has been termed "excitotoxicity" by John Olney. It is known that NMDA receptor-mediated excitotoxicity can be modulated by metabotropic glutamate receptors. However, these receptors are inactivated by hyperammonaemia.
As a consequence of persistent over activation of glutamate receptors during chronic hyperammonaemia, it has been demonstrated in spf mice that NMDA receptors are down-regulated in the cerebral cortex. Although this can be considered as a neuro-protective mechanism, it has severe functional consequences. Synaptic maintenance and plasticity, long-term potentiation, and cognitive functions are all dependent on appropriate glutamatergic neuro-transmission; a silencing of the major excitatory pathway of the brain contributes to long-term cognitive deficits on top of cerebral injury caused by acute hyperammonaemia.
