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. Pathophysiology Excitotoxicity can occur from substances produced within the body (endogenous excitotoxins). Glutamate is a prime example of an excitotoxin in the brain, and it is also the major excitatory neurotransmitter in the central nervous system of mammals. During normal conditions, glutamate concentration can be increased up to 1mM in the synaptic cleft, which is rapidly decreased in the lapse of milliseconds. When the glutamate concentration around the synaptic cleft cannot be decreased or reaches higher levels, the neuron kills itself by a process called apoptosis. This pathologic phenomenon can also occur after brain injury and spinal cord injury. Within minutes after spinal cord injury, damaged neural cells within the lesion site spill glutamate into the extracellular space where glutamate can stimulate presynaptic glutamate receptors to enhance the release of additional glutamate. Brain trauma or stroke can cause ischemia, in which blood flow is reduced to inadequate levels. Ischemia is followed by accumulation of glutamate and aspartate in the extracellular fluid, causing cell death, which is aggravated by lack of oxygen and glucose. The biochemical cascade resulting from ischemia and involving excitotoxicity is called the ischemic cascade. Because of the events resulting from ischemia and glutamate receptor activation, a deep chemical coma may be induced in patients with brain injury to reduce the metabolic rate of the brain (its need for oxygen and glucose) and save energy to be used to remove glutamate actively. (The main aim in induced comas is to reduce the intracranial pressure, not brain metabolism). Increased extracellular glutamate levels leads to the activation of Ca2+ permeable