{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T11:00:04Z","timestamp":1784804404249,"version":"3.55.0"},"reference-count":65,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2017,9,5]],"date-time":"2017-09-05T00:00:00Z","timestamp":1504569600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01MH085666"],"award-info":[{"award-number":["R01MH085666"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009670","name":"National Alliance for Research on Schizophrenia and Depression","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009670","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2017,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>Schizophrenia (<jats:styled-content style=\"fixed-case\">SCZ<\/jats:styled-content>) is characterized not only by psychosis, but also by working memory and executive functioning deficiencies, processes that rely on the prefrontal cortex (<jats:styled-content style=\"fixed-case\">PFC<\/jats:styled-content>). Because these cognitive impairments emerge prior to psychosis onset, we investigated synaptic function during development in the neurodevelopmental methylazoxymethanol (<jats:styled-content style=\"fixed-case\">MAM<\/jats:styled-content>) model for <jats:styled-content style=\"fixed-case\">SCZ<\/jats:styled-content>. Specifically, we hypothesize that N\u2010methyl\u2010D\u2010aspartate receptor (<jats:styled-content style=\"fixed-case\">NMDAR<\/jats:styled-content>) hypofunction is attributable to reductions in the <jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>2B subunit through aberrant epigenetic regulation of gene expression, resulting in deficient synaptic physiology and <jats:styled-content style=\"fixed-case\">PFC<\/jats:styled-content>\u2010dependent cognitive dysfunction, a hallmark of <jats:styled-content style=\"fixed-case\">SCZ<\/jats:styled-content>. Using western blot and whole\u2010cell patch\u2010clamp electrophysiology, we found that the levels of synaptic <jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>2B protein are significantly decreased in juvenile <jats:styled-content style=\"fixed-case\">MAM<\/jats:styled-content> animals, and the function of <jats:styled-content style=\"fixed-case\">NMDAR<\/jats:styled-content>s is substantially compromised. Both <jats:styled-content style=\"fixed-case\">NMDA<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">mEPSC<\/jats:styled-content>s and synaptic <jats:styled-content style=\"fixed-case\">NMDA<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">eEPSC<\/jats:styled-content>s are significantly reduced in prelimbic <jats:styled-content style=\"fixed-case\">PFC<\/jats:styled-content> (pl<jats:styled-content style=\"fixed-case\">PFC<\/jats:styled-content>). This protein loss during the juvenile period is correlated with an aberrant increase in enrichment of the epigenetic transcriptional repressor RE1\u2010silencing transcription factor (REST) and the repressive histone marker H3K27me3 at the <jats:italic>Grin2b<\/jats:italic> promoter, as assayed by Ch<jats:styled-content style=\"fixed-case\">IP<\/jats:styled-content>\u2010quantitative polymerase chain reaction. Glutamate hypofunction has been a prominent hypothesis in the understanding of <jats:styled-content style=\"fixed-case\">SCZ<\/jats:styled-content> pathology; however, little attention has been given to the <jats:styled-content style=\"fixed-case\">NMDAR<\/jats:styled-content> system in the developing <jats:styled-content style=\"fixed-case\">PFC<\/jats:styled-content> in models for <jats:styled-content style=\"fixed-case\">SCZ<\/jats:styled-content>. Our work is the first to confirm that <jats:styled-content style=\"fixed-case\">NMDAR<\/jats:styled-content> hypofunction is a feature of early postnatal development, with epigenetic hyper\u2010repression of the <jats:italic>Grin2b<\/jats:italic> promoter being a contributing factor. The selective loss of <jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>2B protein and subsequent synaptic dysfunction weakens pl<jats:styled-content style=\"fixed-case\">PFC<\/jats:styled-content> function during development and may underlie early cognitive impairments in <jats:styled-content style=\"fixed-case\">SCZ<\/jats:styled-content> models and patients.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc14101-fig-0007-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><jats:p><jats:bold>Read the Editorial Highlight for this article on page<\/jats:bold> <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/doi.org\/10.1111\/jnc.14133\">264<\/jats:ext-link>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.14101","type":"journal-article","created":{"date-parts":[[2017,6,19]],"date-time":"2017-06-19T14:34:36Z","timestamp":1497882876000},"page":"320-333","source":"Crossref","is-referenced-by-count":56,"title":["Epigenetic mechanisms underlying <scp>NMDA<\/scp> receptor hypofunction in the prefrontal cortex of juvenile animals in the <scp>MAM<\/scp> model for schizophrenia"],"prefix":"10.1111","volume":"143","author":[{"given":"Yelena","family":"Gulchina","sequence":"first","affiliation":[{"name":"Department of Neurobiology and Anatomy Drexel University College of Medicine Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song\u2010Jun","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Biology Drexel University Philadelphia Pennsylvania 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