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A recurrent de novo gain-of-function missense mutation (c.1999G>A; p.Val667Ile) was found in multiple patients. The study characterizes a mouse model carrying the orthologous Grin2d mutation using behavioral tasks, electrophysiology in acute cerebellar slices, and electrocorticography to assess activity and drug responses. Grin2d mutants mirror key human phenotypes, including seizures, early motor deficits, cognitive impairment, altered Purkinje neuron development, and abnormal oscillations linked to drug effects.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/a-mouse-model-of-grin2d-developmental-and-epileptic-encephalopathy-recapitulates-the-human-disease/456526/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/a-mouse-model-of-grin2d-developmental-and-epileptic-encephalopathy-recapitulates-the-human-disease/456526.png","ImageObject",300,407,{"name":92,"@type":93},"PakDamar76","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-03","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",12,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What GRIN2D mutation was identified in patients in this study?","Question",{"text":113,"@type":114},"The study reports a recurrent de novo gain-of-function missense variant: c.1999G>A (p.Val667Ile) found in multiple patients.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How was the mouse model of GRIN2D-DEE characterized?",{"text":118,"@type":114},"Researchers used behavioral paradigms, electrophysiological recordings in acute brain slices (with focus on Purkinje neurons), and electrocorticography (ECoG) to monitor brain activity and drug responses.",{"name":120,"@type":111,"acceptedAnswer":121},"Which drug effects were observed in Grin2d mutant mice using ECoG?",{"text":122,"@type":114},"Low-dose ketamine showed limited ECoG spectral effects, while higher ketamine doses triggered seizures. Memantine and phenytoin produced small corrective effects on ECoG properties.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},456526,1790817674,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146,"preview_page_count":4},962090893057,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","[https://doi.org/10.1093/brain/awaf149](https://doi.org/10.1093/brain/awaf149) BRAIN 2026: 149; 90–104 | 90  \nA mouse model of GRIN2D developmental and epileptic encephalopathy recapitulates the human disease  \nMor Yam,1,† Jolan Nassir,1,† Danielle Galber,2,3 Shir Quinn,1 Roni Gal,1,3 Mor Ovadia,3 Mor Bordeynik-Cohen,2 Eden Peled,2 Christopher D. Makinson,4,5,6 Moran Hausman-Kedem,7,8 Aviva Fattal-Valevski,3,7,8 Wayne N. Frankel,6,9  \nKaren B. Avraham2,3 and Moran Rubinstein1,3  \n†These authors contributed equally to this work.  \nPathogenic variants in GRIN2D, encoding one of the subunits of the N-methyl-D-aspartate receptor (NMDAR), are associated with developmental and epileptic encephalopathies (DEEs) . Unusual for de novo mutations, the recurrent, de novo, gain of function, missense mutation c.1999G>A (p.Val667Ile) was discovered in multiple patients. We characterized a mouse model carrying the orthologous Grin2d mutation, using behavioural paradigms, electrophysiological recordings in acute brain slices focusing mainly on the activity of Purkinje neurons in the cerebellum, and electrocorticography (ECoG) recordings monitoring brain activity and the response to several drugs.  \nGrin2d mutant mice exhibit a range of phenotypes that closely mirror the human disease, including premature mortality, spontaneous seizures and early onset of motor deficits followed by cognitive impairment. In addition, we observed complex developmental changes in Purkinje neurons with reduced spontaneous firing in immature mice and augmented synaptic response to NMDA application in older mice. ECoG recordings demonstrated profound and continuous abnormal brain activity, with altered spectral properties and a prominent narrowband activity in the theta, alpha and beta bands, paralleling the patterns seenin a patient with the same GRIN2Dpathogenic variant. Acute administration of ketamine at a low dose (0.5 mg/kg) had a limited effect on the spectral properties, and higher dosages (4 or 10 mg/kg) caused seizures. Conversely, memantine (10 mg/kg) and phenytoin (30 mg/kg) demonstrated a small corrective effect on ECoG properties. Together, Grin2d mutant mice recapitulate key phenotypes of patients with pathogenic GRIN2D variants, including unique, abnormal brain oscillations, which may serve as a biomarker for quantifying drug responses and guiding future research efforts.  \n1 Department of Human Molecular Genetics and Biochemistry and Goldschleger Eye Research Institute, Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv 6139001, Israel  \n2 Department of Human Molecular Genetics and Biochemistry, Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel  \n3 Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 6997801, Israel  \n4 Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032, USA  \n5 Department of Neuroscience, Columbia University Irving Medical Center, New York, NY 10032, USA  \n6 Center for Translational Research in Neurodevelopmental Disease, Columbia University Irving Medical Center, New York, NY 10032, USA  \n7 Pediatric Neurology Institute, Dana-Dwek Children’s Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel  \nReceived October 16, 2024. Revised February 18, 2025. Accepted April 01, 2025. Advance access publication April 25, 2025 © The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain.  \nThis is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ([https://creativecommons.org/licenses/by](https://creativecommons.org/licenses/by)nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [reprints@oup.com](reprints@oup.com) for reprints and translation rights for reprints. All other permissions can be obtained through ou","cbCaiekWwkqhuQPm","https://ap.wps.com/l/cbCaiekWwkqhuQPm","pdf",1608161,15,"English","# Introduction\n## GRIN2D and NMDAR-related DEEs\n# Methods\n## Behavioral paradigms\n## Electrophysiology in acute brain slices\n## Electrocorticography (ECoG) recordings\n# Results\n## Phenotypes in Grin2d mutant mice\n## Purkinje neuron developmental changes\n## Abnormal brain oscillations and drug effects","[{\"question\":\"What GRIN2D mutation was identified in patients in this study?\",\"answer\":\"The study reports a recurrent de novo gain-of-function missense variant: c.1999G\\u003eA (p.Val667Ile) found in multiple patients.\"},{\"question\":\"How was the mouse model of GRIN2D-DEE characterized?\",\"answer\":\"Researchers used behavioral paradigms, electrophysiological recordings in acute brain slices (with focus on Purkinje neurons), and electrocorticography (ECoG) to monitor brain activity and drug responses.\"},{\"question\":\"Which drug effects were observed in Grin2d mutant mice using ECoG?\",\"answer\":\"Low-dose ketamine showed limited ECoG spectral effects, while higher ketamine doses triggered seizures. Memantine and phenytoin produced small corrective effects on ECoG properties.\"}]","A mouse model of GRIN2D developmental and epileptic encephalopathy recapitulates the human disease | PDF",1790746311,38]