Extrasynaptic NMDA receptors are glutamate-gated neurotransmitter receptors that are localized to non-synaptic sites on the neuronal cell surface.[{{Cite journal|last1=Tovar|first1=Kenneth R.|last2=Westbrook|first2=Gary L.|date=2002-04-11|title=Mobile NMDA receptors at hippocampal synapses|journal=Neuron|volume=34|issue=2|pages=255–264|issn=0896-6273|pmid=11970867|doi=10.1016/s0896-6273(02)00658-x|doi-access=free}}][{{Cite journal|last1=Petralia|first1=R. S.|last2=Wang|first2=Y. X.|last3=Hua|first3=F.|last4=Yi|first4=Z.|last5=Zhou|first5=A.|last6=Ge|first6=L.|last7=Stephenson|first7=F. A.|last8=Wenthold|first8=R. J.|date=2010-04-28|title=Organization of NMDA receptors at extrasynaptic locations|journal=Neuroscience|volume=167|issue=1|pages=68–87|doi=10.1016/j.neuroscience.2010.01.022|issn=1873-7544|pmc=2840201|pmid=20096331}}] In contrast to synaptic NMDA receptors that promote acquired neuroprotection and synaptic plasticity, extrasynaptic NMDA receptors are coupled to activation of death-signaling pathways.[{{Cite journal|last1=Hardingham|first1=G. E.|last2=Fukunaga|first2=Y.|last3=Bading|first3=H.|date=2002-05-01|title=Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways|journal=Nature Neuroscience|volume=5|issue=5|pages=405–414|doi=10.1038/nn835|issn=1097-6256|pmid=11953750|s2cid=659716}}] Extrasynaptic NMDA receptors are responsible for initiating excitotoxicity and have been implicated in the etiology of neurodegenerative diseases, including stroke, Huntington’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS).[{{Cite journal|last1=Okamoto|first1=Shu-ichi|last2=Pouladi|first2=Mahmoud A.|last3=Talantova|first3=Maria|last4=Yao|first4=Dongdong|last5=Xia|first5=Peng|last6=Ehrnhoefer|first6=Dagmar E.|last7=Zaidi|first7=Rameez|last8=Clemente|first8=Arjay|last9=Kaul|first9=Marcus|date=2009-12-01|title=Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin|journal=Nature Medicine|volume=15|issue=12|pages=1407–1413|doi=10.1038/nm.2056|issn=1546-170X|pmc=2789858|pmid=19915593}}][{{Cite journal|last1=Milnerwood|first1=Austen J.|last2=Gladding|first2=Clare M.|last3=Pouladi|first3=Mahmoud A.|last4=Kaufman|first4=Alexandra M.|last5=Hines|first5=Rochelle M.|last6=Boyd|first6=Jamie D.|last7=Ko|first7=Rebecca W. Y.|last8=Vasuta|first8=Oana C.|last9=Graham|first9=Rona K.|date=2010-01-28|title=Early increase in extrasynaptic NMDA receptor signaling and expression contributes to phenotype onset in Huntington's disease mice|journal=Neuron|volume=65|issue=2|pages=178–190|doi=10.1016/j.neuron.2010.01.008|issn=1097-4199|pmid=20152125|doi-access=free}}][{{Cite journal|last1=Talantova|first1=Maria|last2=Sanz-Blasco|first2=Sara|last3=Zhang|first3=Xiaofei|last4=Xia|first4=Peng|last5=Akhtar|first5=Mohd Waseem|last6=Okamoto|first6=Shu-ichi|last7=Dziewczapolski|first7=Gustavo|last8=Nakamura|first8=Tomohiro|last9=Cao|first9=Gang|date=2013-07-02|title=Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=110|issue=27|pages=E2518–2527|doi=10.1073/pnas.1306832110|issn=1091-6490|pmc=3704025|pmid=23776240|bibcode=2013PNAS..110E2518T |doi-access=free}}][{{Cite journal|last1=Hardingham|first1=Giles E.|last2=Bading|first2=Hilmar|date=2010-10-01|title=Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders|journal=Nature Reviews. Neuroscience|volume=11|issue=10|pages=682–696|doi=10.1038/nrn2911|issn=1471-0048|pmc=2948541|pmid=20842175}}][{{Cite journal|last1=Parsons|first1=Matthew P.|last2=Raymond|first2=Lynn A.|date=2014-04-16|title=Extrasynaptic NMDA receptor involvement in central nervous system disorders|journal=Neuron|volume=82|issue=2|pages=279–293|doi=10.1016/j.neuron.2014.03.030|issn=1097-4199|pmid=24742457|doi-access=free}}]
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.[{{Cite journal|last1=Yan|first1=Jing|last2=Bengtson|first2=C. Peter|last3=Buchthal|first3=Bettina|last4=Hagenston|first4=Anna M.|last5=Bading|first5=Hilmar|date=9 October 2020|title=Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants|url=https://pubmed.ncbi.nlm.nih.gov/33033186|journal=Science|volume=370|issue=6513|pages=eaay3302|doi=10.1126/science.aay3302|issn=1095-9203|pmid=33033186|s2cid=222210921}}] 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 and retinal ganglion cell degeneration.[{{Cite journal|last1=Yan|first1=Jing|last2=Bengtson|first2=C. Peter|last3=Buchthal|first3=Bettina|last4=Hagenston|first4=Anna M.|last5=Bading|first5=Hilmar|date=9 October 2020|title=Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants|url=https://pubmed.ncbi.nlm.nih.gov/33033186|journal=Science|volume=370|issue=6513|pages=eaay3302|doi=10.1126/science.aay3302|issn=1095-9203|pmid=33033186|s2cid=222210921}}][{{Cite web|title=New Class of Highly Effective Inhibitors Protects against Neurodegeneration – Heidelberg University|url=https://www.uni-heidelberg.de/en/newsroom/new-class-highly-effective-inhibitors-protects-against-neurodegeneration|access-date=2020-10-29|website=www.uni-heidelberg.de}}]