164003 20240319115431.0 10.1523/JNEUROSCI.1689-21.2022 doi pmid:35241491 pmid pmc:PMC8994542 pmc 0270-6474 ISSN 1529-2401 ISSN altmetric:126555880 altmetric DZNE-2022-00672 English 610 Andrzejak, Ewa Izabella P:(DE-2719)2811708 0 First author dzne Patient-Derived Anti-NMDAR Antibody Disinhibits Cortical Neuronal Networks through Dysfunction of Inhibitory Neuron Output. Washington, DC 2022 Soc. article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1677859671_10796 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote (CC BY) Anti-NMDA receptor (NMDAR) encephalitis is a severe neuropsychiatric disorder associated with autoantibodies against NMDARs, which cause a variety of symptoms from prominent psychiatric and cognitive manifestations to seizures and autonomic instability. Previous studies mainly focused on hippocampal effects of these autoantibodies, helping to explain mechanistic causes for cognitive impairment. However, antibodies' effects on higher cortical network function, where they could contribute to psychosis and/or seizures, have not been explored in detail until now. Here, we employed a patient-derived monoclonal antibody targeting the NR1 subunit of NMDAR and tested its effects on in vitro cultures of rodent cortical neurons, using imaging and electrophysiological techniques. We report that this hNR1 antibody drives cortical networks to a hyperexcitable state and disrupts mechanisms stabilizing network activity such as Npas4 signaling. Network hyperactivity is in part a result of a reduced synaptic output of inhibitory neurons, as indicated by a decreased inhibitory drive and levels of presynaptic inhibitory proteins, specifically in inhibitory-to-excitatory neuron synapses. Importantly, on a single-cell level hNR1 antibody selectively impairs NMDAR-mediated currents and synaptic transmission of cortical inhibitory neurons, yet has no effect on excitatory neurons, which contrasts with its effects on hippocampal neurons. Together, these findings provide a novel, cortex-specific mechanism of antibody-induced neuronal hyperexcitability, highlighting regional specificity underlying the pathology of autoimmune encephalitis.SIGNIFICANCE STATEMENT It is increasingly appreciated that the inadvertent activation of the immune system within CNS can underlie pathogenesis of neuropsychiatric disorders. Although the exact mechanisms remain elusive, autoantibodies derived from patients with autoimmune encephalitis pose a unique tool to study pathogenesis of neuropsychiatric states. Our analysis reveals that autoantibody against the NMDA receptor (NMDAR) has a distinct mechanism of action in the cortex, where it impairs function of inhibitory neurons leading to increased cortical network excitability, in contrast to previously described hippocampal synaptic mechanisms of information encoding, highlighting brain regional specificity. Notably, similar mechanism of NMDAR-mediated inhibitory hypofunction leading to cortical disinhibition has been suggested to underlie pathology of schizophrenia, hence our data provide new evidence for common mechanisms underlying neuropsychiatric disorders. 351 - Brain Function (POF4-351) G:(DE-HGF)POF4-351 POF4-351 POF IV 0 353 - Clinical and Health Care Research (POF4-353) G:(DE-HGF)POF4-353 POF4-353 POF IV 1 2022-10-13 Crossref https://creativecommons.org/licenses/by-nc-sa/4.0/ Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de NMDAR Other autoantibodies Other autoimmune encephalitis Other cortical interneurons Other network excitability Other Autoantibodies NLM Chemicals Receptors, N-Methyl-D-Aspartate NLM Chemicals Autoantibodies: metabolism MeSH Encephalitis MeSH Hashimoto Disease MeSH Humans MeSH Neurons: physiology MeSH Receptors, N-Methyl-D-Aspartate: metabolism MeSH Seizures: metabolism MeSH Rabinovitch, Eshed 1 Kreye, Jakob P:(DE-2719)2811468 2 dzne Prüss, Harald P:(DE-2719)2810931 3 dzne Rosenmund, Christian 0000-0002-3905-2444 4 Ziv, Noam E 0000-0001-9197-326X 5 Garner, Craig Curtis P:(DE-2719)2810922 6 dzne Ackermann, Frauke P:(DE-2719)2810967 7 Last author dzne 10.1523/jneurosci.1689-21.2022 Society for Neuroscience 2022-03-03 15 3253-3270 journal-article Crossref The Journal of Neuroscience 42 2022 0270-6474 10.1523/JNEUROSCI.1689-21.2022 Vol. 42, no. 15, p. 3253 - 3270 PERI:(DE-600)1475274-8 15 3253-3270 The journal of neuroscience 42 2022 0270-6474 OpenAccess http://pub.dzne.de/record/164003/files/DZNE-2022-00672.pdf OpenAccess pdfa http://pub.dzne.de/record/164003/files/DZNE-2022-00672.pdf?subformat=pdfa oai:pub.dzne.de:164003 openaire open_access VDB driver dnbdelivery Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 0 P:(DE-2719)2811708 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 2 P:(DE-2719)2811468 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 3 P:(DE-2719)2810931 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 6 P:(DE-2719)2810922 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 7 P:(DE-2719)2810967 DE-HGF Gesundheit Neurodegenerative Diseases G:(DE-HGF)POF4-350 G:(DE-HGF)POF4-351 G:(DE-HGF)POF4 G:(DE-HGF)POF4-300 G:(DE-HGF)POF Brain Function 0 DE-HGF Gesundheit Neurodegenerative Diseases G:(DE-HGF)POF4-350 G:(DE-HGF)POF4-353 G:(DE-HGF)POF4 G:(DE-HGF)POF4-300 G:(DE-HGF)POF Clinical and Health Care Research 1 2022 DBCoverage StatID:(DE-HGF)0200 StatID SCOPUS 2022-11-13 DBCoverage StatID:(DE-HGF)0160 StatID Essential Science Indicators 2021-01-30 DBCoverage StatID:(DE-HGF)1050 StatID BIOSIS Previews 2022-11-13 DBCoverage StatID:(DE-HGF)1190 StatID Biological Abstracts 2021-01-30 DBCoverage StatID:(DE-HGF)0600 StatID Ebsco Academic Search 2022-11-13 JCR StatID:(DE-HGF)0100 StatID J NEUROSCI : 2021 2022-11-13 WoS StatID:(DE-HGF)0113 StatID Science Citation Index Expanded 2021-01-30 DBCoverage StatID:(DE-HGF)1030 StatID Current Contents - Life Sciences 2022-11-13 OpenAccess StatID:(DE-HGF)0510 StatID DBCoverage StatID:(DE-HGF)0150 StatID Web of Science Core Collection 2022-11-13 Peer Review StatID:(DE-HGF)0030 StatID ASC 2022-11-13 IF >= 5 StatID:(DE-HGF)9905 StatID J NEUROSCI : 2021 2022-11-13 DBCoverage StatID:(DE-HGF)0300 StatID Medline 2022-11-13 Creative Commons Attribution CC BY 4.0 LIC:(DE-HGF)CCBY4 HGFVOC DBCoverage StatID:(DE-HGF)0199 StatID Clarivate Analytics Master Journal List 2022-11-13 I:(DE-2719)1810001 AG Garner Synaptopathy 0 I:(DE-2719)1810003 AG Prüß Autoimmune Enzephalopathies 1 I:(DE-2719)1813004 AG Ackermann Astrocyte - Synapse Interaction 2 journal VDB UNRESTRICTED I:(DE-2719)1810001 I:(DE-2719)1810003 I:(DE-2719)1813004 FullTexts -- missing cx lookup -- 10.1523/JNEUROSCI.0187-13.2013 Crossref -- missing cx lookup -- 10.1038/336185a0 Crossref -- missing cx lookup -- 10.1038/nn.2447 Crossref -- missing cx lookup -- 10.1038/361031a0 Crossref -- missing cx lookup -- 10.1038/nature12743 Crossref -- missing cx lookup -- 10.1016/j.neuroscience.2015.10.033 Crossref -- missing cx lookup -- 10.1523/JNEUROSCI.0229-13.2014 Crossref -- missing cx lookup -- 10.1113/jphysiol.2012.227462 Crossref -- missing cx lookup -- 10.1056/NEJMra1708712 Crossref -- missing cx lookup -- 10.1002/ana.21050 Crossref -- missing cx lookup -- 10.7554/eLife.12727 Crossref -- missing cx lookup -- 10.1212/WNL.0000000000007475 Crossref -- missing cx lookup -- 10.1124/mol.113.089334 Crossref -- missing cx lookup -- 10.1523/JNEUROSCI.4980-04.2005 Crossref -- missing cx lookup -- 10.1146/annurev.neuro.31.060407.125631 Crossref -- missing cx lookup -- 10.1523/JNEUROSCI.0064-12.2012 Crossref -- missing cx lookup -- 10.1016/S0166-2236(02)00040-1 Crossref -- missing cx lookup -- 10.3389/fnins.2017.00579 Crossref -- missing cx lookup -- 10.1523/JNEUROSCI.2181-19.2020 Crossref -- missing cx lookup -- 10.1523/JNEUROSCI.2213-07.2007 Crossref -- missing cx lookup -- 10.1523/JNEUROSCI.0167-10.2010 Crossref -- missing cx lookup -- 10.1093/brain/awq113 Crossref -- missing cx lookup -- 10.1186/1471-2202-14-17 Crossref -- missing cx lookup -- 10.1016/S0893-133X(98)00060-8 Crossref -- missing cx lookup -- 10.1111/bph.12127 Crossref -- missing cx lookup -- 10.1126/scitranslmed.aaw0044 Crossref -- missing cx lookup -- 10.1186/s12915-014-0083-3 Crossref -- missing cx lookup -- 10.3389/fneur.2019.00586 Crossref -- missing cx lookup -- 10.1007/s004240050915 Crossref -- missing cx lookup -- 10.1038/s41598-019-41849-z Crossref -- missing cx lookup -- 10.1093/brain/aww208 Crossref -- missing cx lookup -- 10.1001/archpsyc.1994.03950030035004 Crossref -- missing cx lookup -- 10.1523/JNEUROSCI.1245-12.2012 Crossref -- missing cx lookup -- 10.1126/science.1067081 Crossref -- missing cx lookup -- 10.1002/acn3.444 Crossref -- missing cx lookup -- 10.1186/1750-1172-5-31 Crossref -- missing cx lookup -- 10.1371/journal.pone.0017311 Crossref -- missing cx lookup -- 10.1016/S0091-679X(03)01007-0 Crossref -- missing cx lookup -- 10.1093/brain/aws092 Crossref -- missing cx lookup -- 10.1371/journal.pbio.1000136 Crossref -- missing cx lookup -- 10.1002/ana.24195 Crossref -- missing cx lookup -- 10.1016/j.neuropharm.2011.01.022 Crossref -- missing cx lookup -- 10.1016/j.neuron.2016.12.015 Crossref -- missing cx lookup -- 10.1016/j.biopsych.2018.01.018 Crossref -- missing cx lookup -- 10.1093/schbul/sbab030 Crossref -- missing cx lookup -- 10.1093/brain/awu310 Crossref -- missing cx lookup -- 10.1002/ana.24721 Crossref -- missing cx lookup -- 10.1016/j.cell.2014.03.058 Crossref -- missing cx lookup -- 10.1002/cne.10905 Crossref -- missing cx lookup -- 10.1111/epi.14662 Crossref Crossref Teppola H , Okujeni S , Linne ML , Egert U (2018) AMPA, NMDA and GABAA receptor mediated network burst dynamics in cortical cultures in vitro. arXiv:1802.00217. -- missing cx lookup -- 10.3389/fncel.2019.00377 Crossref -- missing cx lookup -- 10.1016/S1474-4422(12)70310-1 Crossref -- missing cx lookup -- 10.1038/nrn2774 Crossref -- missing cx lookup -- 10.1016/j.brainres.2020.147033 Crossref -- missing cx lookup -- 10.1093/brain/awaa250 Crossref -- missing cx lookup -- 10.1126/science.1086907 Crossref -- missing cx lookup -- 10.1093/brain/awv257 Crossref -- missing cx lookup -- 10.1016/j.brainres.2015.12.027 Crossref -- missing cx lookup -- 10.1016/j.nbd.2011.09.019 Crossref -- missing cx lookup -- 10.1152/jn.00079.2008 Crossref