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Patients develop an intrathecal immune response against NMDARs with antibodies that presumably bind to the amino-terminal domain of the GluN1 subunit. The therapeutic response to immunotherapy is often delayed. Therefore, new therapeutic approaches for fast neutralization of NMDAR antibodies are needed. Here, we developed fusion constructs consisting of the Fc part of immunoglobulin G and the amino-terminal domains of either GluN1 or combinations of GluN1 with GluN2A or GluN2B. Surprisingly, both GluN1 and GluN2 subunits were required to generate high-affinity epitopes. The construct with both subunits efficiently prevented NMDAR binding of patient-derived monoclonal antibodies and of patient CSF containing high-titre NMDAR antibodies. Furthermore, it inhibited the internalization of NMDARs in rodent dissociated neurons and human induced pluripotent stem cell-derived neurons. Finally, the construct stabilized NMDAR currents recorded in rodent neurons and rescued memory defects in passive-transfer mouse models using intrahippocampal injections. Our results demonstrate that both GluN1 and GluN2B subunits contribute to the main immunogenic region of the NMDAR and provide a promising strategy for fast and specific treatment of NMDAR encephalitis, which could complement immunotherapy.<\/jats:p>","DOI":"10.1093\/brain\/awac497","type":"journal-article","created":{"date-parts":[[2022,12,28]],"date-time":"2022-12-28T15:38:38Z","timestamp":1672241918000},"page":"1812-1820","source":"Crossref","is-referenced-by-count":27,"title":["NMDA-receptor-Fc-fusion constructs neutralize anti-NMDA receptor antibodies"],"prefix":"10.1093","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8559-954X","authenticated-orcid":false,"given":"Stephan","family":"Steinke","sequence":"first","affiliation":[{"name":"Technische Universit\u00e4t Braunschweig, Institut f\u00fcr Biochemie, Biotechnologie und Bioinformatik, Department Medizinische Biotechnologie , Braunschweig 38106 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1985-5095","authenticated-orcid":false,"given":"Toni","family":"Kirmann","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Carl-Ludwig-Institute of Physiology, Leipzig University , Leipzig 04103 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora A","family":"Loi","sequence":"additional","affiliation":[{"name":"Section Translational Neuroimmunology, Department for Neurology, Jena University Hospital , 07747 Jena , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Nerlich","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Carl-Ludwig-Institute of Physiology, Leipzig University , Leipzig 04103 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iron","family":"Weichard","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Carl-Ludwig-Institute of Physiology, Leipzig University , Leipzig 04103 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Kuhn","sequence":"additional","affiliation":[{"name":"YUMAB GmbH , Braunschweig 38124 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torsten","family":"Bullmann","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Carl-Ludwig-Institute of Physiology, Leipzig University , Leipzig 04103 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Ritzau-Jost","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Carl-Ludwig-Institute of Physiology, Leipzig University , Leipzig 04103 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filiz Sila","family":"Rizalar","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharamcology and Cell Biology, Leibniz-Forschungsinstitut f\u00fcr Molekulare Pharmakologie (FMP) , 13125 Berlin , Germany"},{"name":"Faculty of Biology, Chemistry, Pharmacy, Freie Universit\u00e4t Berlin , Berlin 14195 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"Pr\u00fcss","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE) Berlin , Berlin 10117 , Germany"},{"name":"Department of Neurology and Experimental Neurology, Charit\u00e9-Universit\u00e4tsmedizin Berlin , 10117 Berlin , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volker","family":"Haucke","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharamcology and Cell Biology, Leibniz-Forschungsinstitut f\u00fcr Molekulare Pharmakologie (FMP) , 13125 Berlin , Germany"},{"name":"Faculty of Biology, Chemistry, Pharmacy, Freie Universit\u00e4t Berlin , Berlin 14195 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9859-581X","authenticated-orcid":false,"given":"Christian","family":"Geis","sequence":"additional","affiliation":[{"name":"Section Translational Neuroimmunology, Department for Neurology, Jena University Hospital , 07747 Jena , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3418-6045","authenticated-orcid":false,"given":"Michael","family":"Hust","sequence":"additional","affiliation":[{"name":"Technische Universit\u00e4t Braunschweig, Institut f\u00fcr Biochemie, Biotechnologie und Bioinformatik, Department Medizinische Biotechnologie , Braunschweig 38106 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9376-7048","authenticated-orcid":false,"given":"Stefan","family":"Hallermann","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Carl-Ludwig-Institute of 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