{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T05:17:07Z","timestamp":1790054227968,"version":"4.0.1"},"reference-count":79,"publisher":"Wiley","issue":"20","license":[{"start":{"date-parts":[[2018,9,19]],"date-time":"2018-09-19T00:00:00Z","timestamp":1537315200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100004836","name":"Det Frie Forskningsr\u00e5d","doi-asserted-by":"publisher","award":["DFF \u2010 4004\u201000188"],"award-info":[{"award-number":["DFF \u2010 4004\u201000188"]}],"id":[{"id":"10.13039\/501100004836","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003554","name":"Lundbeckfonden","doi-asserted-by":"publisher","award":["2011\u20108826"],"award-info":[{"award-number":["2011\u20108826"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2018,10]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Fragile X syndrome (FXS) is a genetic condition that is the most common form of inherited intellectual impairment and causes a range of neurodevelopmental complications including learning disabilities and intellectual disability and shares many characteristics with autism spectrum disorder (ASD).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In the FXS mouse model, <jats:italic>Fmr1<jats:sup>\u2212\/y<\/jats:sup><\/jats:italic>, impaired synaptic plasticity was restored by pharmacologically inhibiting GluN2A\u2010containing NMDA receptors but not GluN2B\u2010containing receptors.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Similar results were obtained by crossing <jats:italic>Fmr1<jats:sup>\u2212\/y<\/jats:sup><\/jats:italic> with GluN2A knock\u2010out (<jats:italic>Grin2A<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic>) mice.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These results suggest that dampening the elevated levels of GluN2A\u2010containing NMDA receptors in <jats:italic>Fmr1<jats:sup>\u2212\/y<\/jats:sup><\/jats:italic> mice has the potential to restore hyperexcitability of the neural circuitry to (a more) normal\u2010like level of brain activity.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>NMDA receptors (NMDARs) play important roles in synaptic plasticity at central excitatory synapses, and dysregulation of their function may lead to severe disorders such Fragile X syndrome (FXS). FXS is caused by transcriptional silencing of the FMR1 gene followed by lack of the encoding protein. Here we examined the effects of pharmacological and genetic manipulation of hippocampal NMDAR functions in long\u2010term potentiation (LTP) and depression (LTD). We found impaired NMDAR\u2010dependent LTP in the Fmr1\u2010deficient mice, which could be fully restored when GluN2A\u2010containing NMDARs was pharmacological inhibited. Interestingly, similar LTP effects were observed when the GluN2A gene (<jats:italic>Grin2a<\/jats:italic>) was deleted in <jats:italic>Fmr1<jats:sup>\u2212\/y<\/jats:sup><\/jats:italic> mice (<jats:italic>Fmr1<jats:sup>\u2212\/y<\/jats:sup><\/jats:italic>\/<jats:italic>Grin2a<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> double knockout). In addition, GluN2A inhibition improved elevated mGluR5\u2010dependent LTD to normal level in the <jats:italic>Fmr1<jats:sup>\u2212\/y<\/jats:sup><\/jats:italic> mouse. These findings suggest that GluN2A is a promising target in FXS research that could help us better understand the disorder.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp276304","type":"journal-article","created":{"date-parts":[[2018,8,22]],"date-time":"2018-08-22T16:36:58Z","timestamp":1534955818000},"page":"5017-5031","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Inhibition of GluN2A NMDA receptors ameliorates synaptic plasticity deficits in the <i>Fmr1<sup>\u2212\/y<\/sup><\/i> mouse model"],"prefix":"10.1113","volume":"596","author":[{"given":"Camilla J.","family":"Lundbye","sequence":"first","affiliation":[{"name":"Institute of Biomedicine \u2013 Physiology Aarhus University  DK\u20108000 Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Karina H.","family":"Toft","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine \u2013 Physiology Aarhus University  DK\u20108000 Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8417-4400","authenticated-orcid":false,"given":"Tue G.","family":"Banke","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine \u2013 Physiology Aarhus University  DK\u20108000 Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,9,19]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/6338"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.1992.tb00900.x"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3639-07.2008"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1087-15.2015"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2006.07.013"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2008.10.004"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2006.07.016"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1905-05.2005"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.110.172544"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.12488"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.7909958"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2016.06.033"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2014.11.008"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1994.tb13057.x"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2017.09.026"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(01)00036-7"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2009.09.007"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0705861"},{"key":"e_1_2_5_20_1","first-page":"23","article-title":"Fmr1 knockout mice: a model to study fragile X mental retardation","volume":"78","author":"The Dutch\u2010Belgian Fragile X Consortium","year":"1994","journal-title":"Cell"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.06.017"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.01.005"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.06.013"},{"key":"e_1_2_5_24_1","first-page":"1530","article-title":"The translation of translational control by FMRP: therapeutic targets for FXS","volume":"16","author":"Darnell JC","year":"2013","journal-title":"Nat Publ Gr"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00221.2006"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2008.150722"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2010.01.005"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1014888505185"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(96)12301-6"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80442-0"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19960809)64:2<246::AID-AJMG2>3.0.CO;2-S"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP270818"},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-15028-x"},{"key":"e_1_2_5_34_1","first-page":"3","volume-title":"Fragile X Syndrome: Diagnosis, Treatment, and Research","author":"Hagerman RJ","year":"1996"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5757-11.2012"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1993.tb13733.x"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.122205699"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(06)70676-7"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.18-17-06704.1998"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-34-10791.2003"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2624-07.2007"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.09.033"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2006.08.023"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1006\/mcne.2001.1085"},{"key":"e_1_2_5_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3192"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1096615"},{"key":"e_1_2_5_47_1","first-page":"1","article-title":"NMDA receptor\u2010dependent long\u2010term potentiation and long\u2010term depression (LTP \/ LTD)","volume":"4","author":"Lu C","year":"2012","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"e_1_2_5_48_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00585965"},{"key":"e_1_2_5_49_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.285.5435.1870"},{"key":"e_1_2_5_50_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1697-04.2004"},{"key":"e_1_2_5_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2007.04.028"},{"key":"e_1_2_5_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.03.009"},{"key":"e_1_2_5_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2006.07.005"},{"key":"e_1_2_5_54_1","first-page":"264","article-title":"Selective impairment of learning and blockage of long\u2010term potentiation by an N\u2010methyl\u2010d\u2010aspartate receptor antagonist, AP5","volume":"320","author":"Morris RGM","year":"1986","journal-title":"Nature"},{"key":"e_1_2_5_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2303"},{"key":"e_1_2_5_56_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.21-14-05139.2001"},{"key":"e_1_2_5_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80336-0"},{"key":"e_1_2_5_58_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3888-10.2010"},{"key":"e_1_2_5_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3504"},{"key":"e_1_2_5_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(99)00285-7"},{"key":"e_1_2_5_61_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.182600"},{"key":"e_1_2_5_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/373151a0"},{"key":"e_1_2_5_63_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.042663"},{"key":"e_1_2_5_64_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2009.06314.x"},{"key":"e_1_2_5_65_1","doi-asserted-by":"publisher","DOI":"10.1186\/1756-6606-6-15"},{"key":"e_1_2_5_66_1","doi-asserted-by":"publisher","DOI":"10.1002\/aur.168"},{"key":"e_1_2_5_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80921-6"},{"key":"e_1_2_5_68_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3038-15.2016"},{"key":"e_1_2_5_69_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0829-13.2013"},{"key":"e_1_2_5_70_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19960712)64:1<196::AID-AJMG35>3.0.CO;2-G"},{"key":"e_1_2_5_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(91)90397-H"},{"key":"e_1_2_5_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2013.01.016"},{"key":"e_1_2_5_73_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1014-09.2009"},{"key":"e_1_2_5_74_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1601-183X.2004.00087.x"},{"key":"e_1_2_5_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2005.06.004"},{"key":"e_1_2_5_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2008.07.046"},{"key":"e_1_2_5_77_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.115.097998"},{"key":"e_1_2_5_78_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(03)00079-5"},{"key":"e_1_2_5_79_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2006.05.010"},{"key":"e_1_2_5_80_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1520-05.2005"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1113%2FJP276304","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP276304","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,16]],"date-time":"2023-09-16T22:58:59Z","timestamp":1694905139000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP276304"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,9,19]]},"references-count":79,"journal-issue":{"issue":"20","published-print":{"date-parts":[[2018,10]]}},"alternative-id":["10.1113\/JP276304"],"URL":"https:\/\/doi.org\/10.1113\/jp276304","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,9,19]]},"assertion":[{"value":"2018-07-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-08-20","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-09-19","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}