It is now generally accepted that glutamate is the main fast excitatory neurotransmitter in the mammalian central nervous system (CNS). Glutamate activates the major ionotropic receptors, namely α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, and NMDA as well as several types of metabotropic receptors. AMPA receptors are probably involved in all forms of fast glutamatergic neurotransmission. NMDA receptors are activated only following depolarization of the postsynaptic membrane, which physiologically follows AMPA receptor stimulation that relieves blockade by Mg2+. This unique feature and their high Ca2+ permeability render NMDA receptors inherently suitable as mediators of synaptic plasticity (e.g., learning and memory). During normal synaptic activity, large concentrations of glutamate are released, the postsynaptic membrane is depolarized, the Mg2+ blockade is transiently removed, Ca2+ ions enter the cell, and a signal is generated. Under conditions of impaired metabolism, there is sustained release of glutamate leading to ‘excitotoxicity’ in which the Mg2+ ions are lost from the NMDA receptors, allowing a continuous influx of Ca2+ ions into the cell. This creates a high level of background noise that impairs recognition of the signals generated by physiological activation of the receptor. High intracellular concentrations of Ca2+ eventually lead to neuronal degeneration and cell death, as is observed in many types of acute and chronic neurodegenerative disorders of the CNS. Disturbance of glutamate homeostasis probably also plays a pivotal role in the neuropathology triggered by other factors, such as energy deficit and formation of free radicals, that facilitate the neurotoxic potential of endogenous glutamate. There is evidence in Alzheimer’s disease of increased levels of glutamate (caused by decreased cellular uptake and/or increased release) or other endogenous glutamate-receptor agonists in the vicinity of neurons, and amyloid-beta peptide either activates NMDA receptors or enhances their sensitivity.

by Serge Gauthier