Extrasynaptic NMDA receptors are glutamate-gatedneurotransmitter receptors that are localized to non-synaptic sites on theneuronalcell surface.^[1][2] In contrast to synaptic NMDA receptors that promoteacquired neuroprotection andsynaptic plasticity, extrasynaptic NMDA receptors are coupled to activation of death-signaling pathways.^[3] Extrasynaptic NMDA receptors are responsible for initiatingexcitotoxicity and have been implicated in the etiology ofneurodegenerative diseases, includingstroke,Huntington’s disease,Alzheimer’s disease, andamyotrophic lateral sclerosis (ALS).^{[4][5][6][7][8]}

Extrasynaptic NMDA receptors form a death signaling complex with the transient receptor potential cation channel subfamily M member 4 (TRPM4). The NMDAR/TRPM4 complex is considered central to glutamate excitotoxicity.^[9] NMDAR/TRPM4 interaction interface inhibitors (also known as 'interface inhibitors') disrupt the NMDAR/TRPM4 complex thereby detoxifying extrasynaptic NMDA receptors. In mouse disease models, interface inhibitors protect against stroke induced brain damage andretinal ganglion cell degeneration.^[10][11]

• Molecular neuroscience