Glutamatergic neurons form the major excitatory system in the brain and play a pivotal role in many physiological functions. Apart from the physiological role of glutamate, excessive activation of its receptors can also evoke neuronal dysfunction and even damage/death. Cell death ascribed to an excessive activation of glutamate receptors has been termed 'excitotoxicity' and seems to occur in acute insults such as stroke and trauma, but it may be also associated with chronic neurodegenerative diseases such as Alzheimer disease. N-methyl-D-aspartate (NMDA) receptor (NMDAR) mediated glutamate excitotoxicity is thought to play a major role in Aβ-induced neuronal death. This idea is part of the foundation of the glutamatergic hypothesis (as opposed to the cholinergic hypothesis) for Alzheimer disease.