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We have previously shown that blocking <jats:styled-content style=\"fixed-case\">NMDAR<\/jats:styled-content>\u2010 post\u2010synaptic density\u201095 (<jats:styled-content style=\"fixed-case\">PSD<\/jats:styled-content>95) interactions provides significant protection from excitotoxicity and <jats:italic>in vivo<\/jats:italic> ischaemia; however, the mechanism of neuroprotection is unclear. Here, we report that blocking <jats:styled-content style=\"fixed-case\">PSD<\/jats:styled-content>\u201095 interactions with the Tat\u2010<jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>2B9c peptide enhances a Ca<jats:sup>2<\/jats:sup>\u00a0<jats:sup>+<\/jats:sup>\u00a0\u2010dependent protective pathway converging on cAMP Response Element binding protein (<jats:styled-content style=\"fixed-case\">CREB<\/jats:styled-content>) activation. We provide evidence that Tat\u2010<jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>2B9c neuroprotection from oxygen glucose deprivation and <jats:styled-content style=\"fixed-case\">NMDA<\/jats:styled-content> toxicity occurs in parallel with the activation of calmodulin kinase signalling and is dependent on a sustained phosphorylation of the <jats:styled-content style=\"fixed-case\">CREB<\/jats:styled-content> transcription factor and its activator Ca<jats:styled-content style=\"fixed-case\">MKIV<\/jats:styled-content>. Tat\u2010<jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>2B9c\u2010dependent neuroprotection and <jats:styled-content style=\"fixed-case\">CREB<\/jats:styled-content> phosphorylation are blocked by coapplication of CaM kinase (<jats:styled-content style=\"fixed-case\">KN<\/jats:styled-content>93 and <jats:styled-content style=\"fixed-case\">STO<\/jats:styled-content>\u2010609) or <jats:styled-content style=\"fixed-case\">CREB<\/jats:styled-content> (<jats:styled-content style=\"fixed-case\">KG<\/jats:styled-content>\u2010501) inhibitors, and by si<jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content> knockdown of Ca<jats:styled-content style=\"fixed-case\">MKIV<\/jats:styled-content>. These results are mirrored <jats:italic>in vivo<\/jats:italic> in a rat model of permanent focal ischaemia. Tat\u2010<jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>2B9c application significantly reduces infarct size and causes a selective and sustained elevation in Ca<jats:styled-content style=\"fixed-case\">MKIV<\/jats:styled-content> phosphorylation; effects which are blocked by coadministration of <jats:styled-content style=\"fixed-case\">KN<\/jats:styled-content>93. Thus, calcium\u2010dependent nuclear signalling via Ca<jats:styled-content style=\"fixed-case\">MKIV<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">CREB<\/jats:styled-content> is critical for neuroprotection via <jats:styled-content style=\"fixed-case\">NMDAR<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">PSD<\/jats:styled-content>95 blockade, both <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. This study highlights the importance of maintaining neuronal function following ischaemic injury. Future stroke research should target neurotrophic and pro\u2010survival signal pathways in the development of novel neuroprotective strategies.<\/jats:p>","DOI":"10.1111\/jnc.12176","type":"journal-article","created":{"date-parts":[[2013,1,31]],"date-time":"2013-01-31T13:06:17Z","timestamp":1359637577000},"page":"274-287","source":"Crossref","is-referenced-by-count":57,"title":["Calmodulin Kinase <scp>IV<\/scp>\u2013dependent <scp>CREB<\/scp> activation is required for neuroprotection via <scp>NMDA<\/scp> receptor\u2010<scp>PSD<\/scp>95 disruption"],"prefix":"10.1111","volume":"126","author":[{"given":"Karen F. S.","family":"Bell","sequence":"first","affiliation":[{"name":"Department of Biological Sciences University of Toronto Scarborough Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell J.","family":"Bent","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences University of Toronto Scarborough Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saira","family":"Meese\u2010Tamuri","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences University of Toronto Scarborough Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences University of Toronto Scarborough Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joan P.","family":"Forder","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences University of Toronto Scarborough Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle M.","family":"Aarts","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences University of Toronto Scarborough Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,3,3]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1072873"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(03)01017-1"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3290-04.2004"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/1744-8069-2-15"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.2174\/156802606777323700"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/35081080"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.17.6.1304"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0406374101"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81816-4"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2011.01.025"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2007.05.008"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-4388(97)80065-7"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1469-10.2010"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0969-9961(02)00016-5"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2002.01080.x"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-0173(00)00018-7"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10841"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1464-07.2007"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.31.2.347"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80026-4"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.127654"},{"key":"e_1_2_8_23_1","doi-asserted-by":"crossref","first-page":"15520","DOI":"10.1016\/S0021-9258(17)40710-1","article-title":"Characterization of Ca2\u00a0+\u00a0\/calmodulin\u2010dependent protein kinase IV. 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