{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,2]],"date-time":"2025-08-02T05:05:16Z","timestamp":1754111116030,"version":"3.37.3"},"reference-count":9,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2023,2,11]],"date-time":"2023-02-11T00:00:00Z","timestamp":1676073600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,2,11]],"date-time":"2023-02-11T00:00:00Z","timestamp":1676073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["CRC 1436 A02","Z01 FOR5528 RP6","CRC1436 A02 FOR 5228 RP6"],"award-info":[{"award-number":["CRC 1436 A02","Z01 FOR5528 RP6","CRC1436 A02 FOR 5228 RP6"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004412","name":"Human Frontier Science Program","doi-asserted-by":"publisher","award":["HFSP RGP0002\/2022"],"award-info":[{"award-number":["HFSP RGP0002\/2022"]}],"id":[{"id":"10.13039\/100004412","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001664","name":"Leibniz-Gemeinschaft","doi-asserted-by":"publisher","award":["SynERca","Neurotranslation","SyMetAge"],"award-info":[{"award-number":["SynERca","Neurotranslation","SyMetAge"]}],"id":[{"id":"10.13039\/501100001664","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005156","name":"Alexander von Humboldt-Stiftung","doi-asserted-by":"publisher","award":["99999.001756\/2014-01"],"award-info":[{"award-number":["99999.001756\/2014-01"]}],"id":[{"id":"10.13039\/100005156","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Land Saxony Anhalt","award":["Development Fund (ERDF 2014 - 2020)ZS\/2016\/04\/78113","ZS\/2016\/04\/78120"],"award-info":[{"award-number":["Development Fund (ERDF 2014 - 2020)ZS\/2016\/04\/78113","ZS\/2016\/04\/78120"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Brain"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Jacob is a synapto-nuclear messenger protein that encodes and transduces the origin of synaptic and extrasynaptic NMDA receptor signals to the nucleus. The protein assembles a signalosome that differs in case of synaptic or extrasynaptic NMDAR activation. Following nuclear import Jacob docks these signalosomes to the transcription factor CREB. We have recently shown that amyloid-\u03b2 and extrasynaptic NMDAR activation triggers the translocation of a Jacob signalosome that results in inactivation of the transcription factor CREB, a phenomenon termed Jacob-induced CREB shut-off (JaCS). JaCS contributes to early Alzheimer\u2019s disease pathology and the absence of Jacob protects against amyloid pathology. Given that extrasynaptic activity is also involved in acute excitotoxicity, like in stroke, we asked whether nsmf gene knockout will also protect against acute insults, like oxygen and glucose deprivation and excitotoxic NMDA stimulation. nsmf is the gene that encodes for the Jacob protein. Here we show that organotypic hippocampal slices from wild-type and nsmf<jats:sup>\u2212\/\u2212<\/jats:sup>mice display similar degrees of degeneration when exposed to either oxygen glucose deprivation or 50\u00a0\u00b5M NMDAto induce excitotoxicity. This lack of neuroprotection indicates that JaCS is mainly relevant in conditions of low level chronic extrasynaptic NMDAR activation that results in cellular degeneration induced by alterations in gene transcription.<\/jats:p>","DOI":"10.1186\/s13041-023-01012-2","type":"journal-article","created":{"date-parts":[[2023,2,11]],"date-time":"2023-02-11T11:03:22Z","timestamp":1676113402000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Jacob\/nsmf gene knockout does not protect against acute hypoxia- and NMDA-induced excitotoxic cell death"],"prefix":"10.1186","volume":"16","author":[{"given":"Guilherme M.","family":"Gomes","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"B\u00e4r","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Karpova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0575-6950","authenticated-orcid":false,"given":"Michael R.","family":"Kreutz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,2,11]]},"reference":[{"key":"1012_CR1","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1515\/rns.2011.018","volume":"22","author":"CA Saura","year":"2011","unstructured":"Saura CA, Valero J. The role of CREB signaling in Alzheimer\u2019s disease and other cognitive disorders. Rev Neurosci. 2011;22:153\u201369.","journal-title":"Rev Neurosci"},{"issue":"5","key":"1012_CR2","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.1016\/j.cell.2013.02.002","volume":"152","author":"A Karpova","year":"2013","unstructured":"Karpova A, Mikhaylova M, Bera S, B\u00e4r J, Reddy PP, Behnisch T, Rankovic V, Spilker C, Bethge P, Sahin J, Kaushik R, Zuschratter W, K\u00e4hne T, Naumann M, Gundelfinger ED, Kreutz MR. Encoding and transducing the synaptic or extrasynaptic origin of NMDA receptors signals to the nucleus. Cell. 2013;152(5):1119\u201333.","journal-title":"Cell"},{"doi-asserted-by":"crossref","unstructured":"Grochowska KM, Gomes GM, Raman R, Kaushik R, Sosulina L, Kaneko H, Oelschlegel AM, Yuanxiang P, Reyes-Resina I, Bayraktar G, Samer S, Spilker C, Woo MS, Morawski M, Goldschmidt J, Friese MA, Rossner S, Brugal GM, Remy S, Reissner C, Karpova A, Kreutz MR. Preventing Jacob-induced transcriptional inactivation of CREB protects synapses from \u03b2-amyloid in Alzheimer\u2019s disease. EMBO Journal 2023;e112453.","key":"1012_CR3","DOI":"10.15252\/embj.2022112453"},{"key":"1012_CR4","doi-asserted-by":"publisher","first-page":"2029","DOI":"10.1038\/s41418-021-00814-y","volume":"28","author":"D Moujalled","year":"2021","unstructured":"Moujalled D, Strasser A, Liddell JR. Molecular mechanisms of cell death in neurological diseases. Cell Death Differ. 2021;28:2029\u201344.","journal-title":"Cell Death Differ"},{"issue":"3","key":"1012_CR5","doi-asserted-by":"publisher","first-page":"1005907","DOI":"10.1371\/journal.pgen.1005907","volume":"12","author":"C Spilker","year":"2016","unstructured":"Spilker C, Nullmeier S, Grochowska KM, Schumacher A, Butnaru I, Macharadze T, Gomes GM, Yuanxiang P, Bayraktar G, Rodenstein C, Geiseler C, Kolodjziej A, Lopez-Rojas J, Montag D, Angenstein F, B\u00e4r J, D\u2019Hanis W, Roskoden T, Mikhaylova M, Budinger E, Ohl FW, Stork O, Zenclussen AC, Karpova A, Schwegler H, Kreutz MR. A Jacob\/nsmf gene knockout results in hippocampal dysplasia and impaired BDNF signaling in dendritogenesis. PLoS Genet. 2016;12(3):1005907.","journal-title":"PLoS Genet"},{"key":"1012_CR6","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/nn835","volume":"5","author":"GE Hardingham","year":"2002","unstructured":"Hardingham GE, Fukunaga Y, Bading H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci. 2002;5:405\u201314.","journal-title":"Nat Neurosci"},{"issue":"10","key":"1012_CR7","doi-asserted-by":"publisher","first-page":"2595","DOI":"10.1111\/j.1460-9568.2006.04786.x","volume":"23","author":"CE Gee","year":"2006","unstructured":"Gee CE, Benquet P, Raineteau O, Rietschin L, Kirbach SW, Gerber U. NMDA Receptors and the differential ischemic vulnerability of hippocampal neurons. Eur J Neurosci. 2006;23(10):2595\u2013603.","journal-title":"Eur J Neurosci"},{"key":"1012_CR8","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1016\/j.neuropharm.2012.12.002","volume":"67","author":"G Maraula","year":"2013","unstructured":"Maraula G, Traini C, Mello T, Coppi E, Galli A, Pedata F, Publiese AM. Effects of oxygen and glucose deprivation on synaptic transmission in rat dentate gyrus: role of A2A adenosine receptors. Neuropharmacology. 2013;67:511\u201320.","journal-title":"Neuropharmacology"},{"issue":"7","key":"1012_CR9","doi-asserted-by":"publisher","first-page":"1413","DOI":"10.1007\/s10571-020-00924-0","volume":"41","author":"RG Mira","year":"2021","unstructured":"Mira RG, Cerpa W. Building a bridge between NMDAR-mediated excitotoxicity and mitochondrial dysfunction in chronic and acute diseases. Cell Mol Neurobiol. 2021;41(7):1413\u201330.","journal-title":"Cell Mol Neurobiol"}],"container-title":["Molecular Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13041-023-01012-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13041-023-01012-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13041-023-01012-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,6]],"date-time":"2023-12-06T18:29:49Z","timestamp":1701887389000},"score":1,"resource":{"primary":{"URL":"https:\/\/molecularbrain.biomedcentral.com\/articles\/10.1186\/s13041-023-01012-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,11]]},"references-count":9,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["1012"],"URL":"https:\/\/doi.org\/10.1186\/s13041-023-01012-2","relation":{},"ISSN":["1756-6606"],"issn-type":[{"type":"electronic","value":"1756-6606"}],"subject":[],"published":{"date-parts":[[2023,2,11]]},"assertion":[{"value":"26 December 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 February 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 February 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Experiments were conducted following ethical animal research standards defined by the German Law\/European directive and approved by the Landesverwaltungsamt Saxony-Anhalt (Referat 203, Verbraucherschutz und Veterin\u00e4rangelegenheiten). The competent authority follows the advice of an official animal welfare committee of the Federal State of Saxony-Anhalt, Germany.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"23"}}