The harmful effects of glutamate on the central nervous system were first observed in 1954 by T. Hayashi, a Japanese scientist who stated that direct application of glutamate caused seizure activity, though this report went unnoticed for several years. D. R. Lucas and J. P. Newhouse, after noting that "single doses of [20–30 grams of sodium glutamate in humans] have ... been administered intravenously without permanent ill-effects", observed in 1957 that a subcutaneous dose described as "a little less than lethal", destroyed the neurons in the inner layers of the retina in newborn mice. In 1969, John Olney discovered that the phenomenon was not restricted to the retina, but occurred throughout the brain, and coined the term excitotoxicity. He also assessed that cell death was restricted to postsynaptic neurons, that glutamate agonists were as neurotoxic as their efficiency to activate glutamate receptors, and that glutamate antagonists could stop the neurotoxicity.
In 2002, Hilmar Bading and co-workers found that excitotoxicity is caused by the activation of NMDA receptors located outside synaptic contacts. The molecular basis for toxic extrasynaptic NMDA receptor signaling was uncovered in 2020 when Hilmar Bading and co-workers described a death signaling complex that consists of extrasynaptic NMDA receptor and TRPM4. Disruption of this complex using NMDAR/TRPM4 interface inhibitors (also known as ‚interface inhibitors‘) renders extrasynaptic NMDA receptor non-toxic.