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The disease mechanism involves a pathological triad consisting of mitochondrial dysfunction, loss of integrity of neuronal structures and connectivity, and disruption of excitation\u2013transcription coupling caused by CREB (cyclic adenosine monophosphate\u2013responsive element-binding protein) shut-off and nuclear accumulation of class IIa histone deacetylases. Interdependency within the triad fuels an accelerating disease progression that culminates in failure of mitochondrial energy production and cell loss. Both acute and slowly progressive neurodegenerative conditions, including stroke, Alzheimer\u2019s disease, amyotrophic lateral sclerosis, and Huntington\u2019s disease, share increased death signaling by extrasynaptic NMDA receptors caused by elevated extracellular glutamate concentrations or relocalization of NMDA receptors to extrasynaptic sites. Six areas of therapeutic objectives are defined, based on which a broadly applicable combination therapy is proposed to combat the pathological triad of extrasynaptic NMDA receptor signaling that is common to many neurodegenerative diseases.<\/jats:p>","DOI":"10.1084\/jem.20161673","type":"journal-article","created":{"date-parts":[[2017,2,16]],"date-time":"2017-02-16T16:30:11Z","timestamp":1487262611000},"page":"569-578","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":149,"title":["Therapeutic targeting of the pathological triad of extrasynaptic NMDA receptor signaling in neurodegenerations"],"prefix":"10.1084","volume":"214","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0258-4348","authenticated-orcid":true,"given":"Hilmar","family":"Bading","sequence":"first","affiliation":[{"name":"Department of Neurobiology, Interdisciplinary Center for Neurosciences, Heidelberg University, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2017,2,16]]},"reference":[{"key":"2023072609115105100_bib1","doi-asserted-by":"publisher","first-page":"9970","DOI":"10.1074\/jbc.M113.502914","article-title":"The nuclear calcium signaling target, activating transcription factor 3 (ATF3), protects against dendrotoxicity and facilitates the recovery of synaptic transmission after an excitotoxic insult","volume":"289","author":"Ahlgren","year":"2014","journal-title":"J. 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