PMID- 25392198 OWN - NLM STAT- MEDLINE DCOM- 20150302 LR - 20220331 IS - 1460-2156 (Electronic) IS - 0006-8950 (Print) IS - 0006-8950 (Linking) VI - 138 IP - Pt 1 DP - 2015 Jan TI - Human N-methyl D-aspartate receptor antibodies alter memory and behaviour in mice. PG - 94-109 LID - 10.1093/brain/awu310 [doi] AB - Anti-N-methyl D-aspartate receptor (NMDAR) encephalitis is a severe neuropsychiatric disorder that associates with prominent memory and behavioural deficits. Patients' antibodies react with the N-terminal domain of the GluN1 (previously known as NR1) subunit of NMDAR causing in cultured neurons a selective and reversible internalization of cell-surface receptors. These effects and the frequent response to immunotherapy have suggested an antibody-mediated pathogenesis, but to date there is no animal model showing that patients' antibodies cause memory and behavioural deficits. To develop such a model, C57BL6/J mice underwent placement of ventricular catheters connected to osmotic pumps that delivered a continuous infusion of patients' or control cerebrospinal fluid (flow rate 0.25 microl/h, 14 days). During and after the infusion period standardized tests were applied, including tasks to assess memory (novel object recognition in open field and V-maze paradigms), anhedonic behaviours (sucrose preference test), depressive-like behaviours (tail suspension, forced swimming tests), anxiety (black and white, elevated plus maze tests), aggressiveness (resident-intruder test), and locomotor activity (horizontal and vertical). Animals sacrificed at Days 5, 13, 18, 26 and 46 were examined for brain-bound antibodies and the antibody effects on total and synaptic NMDAR clusters and protein concentration using confocal microscopy and immunoblot analysis. These experiments showed that animals infused with patients' cerebrospinal fluid, but not control cerebrospinal fluid, developed progressive memory deficits, and anhedonic and depressive-like behaviours, without affecting other behavioural or locomotor tasks. Memory deficits gradually worsened until Day 18 (4 days after the infusion stopped) and all symptoms resolved over the next week. Accompanying brain tissue studies showed progressive increase of brain-bound human antibodies, predominantly in the hippocampus (maximal on Days 13-18), that after acid extraction and characterization with GluN1-expressing human embryonic kidney cells were confirmed to be against the NMDAR. Confocal microscopy and immunoblot analysis of the hippocampus showed progressive decrease of the density of total and synaptic NMDAR clusters and total NMDAR protein concentration (maximal on Day 18), without affecting the post-synaptic density protein 95 (PSD95) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. These effects occurred in parallel with memory and other behavioural deficits and gradually improved after Day 18, with reversibility of symptoms accompanied by a decrease of brain-bound antibodies and restoration of NMDAR levels. Overall, these findings establish a link between memory and behavioural deficits and antibody-mediated reduction of NMDAR, provide the biological basis by which removal of antibodies and antibody-producing cells improve neurological function, and offer a model for testing experimental therapies in this and similar disorders. CI - (c) The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com. FAU - Planaguma, Jesus AU - Planaguma J AD - 1 Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Universitat de Barcelona, Barcelona, Spain 2 ICFO-Institut de Ciencies Fotoniques, Barcelona, Spain. FAU - Leypoldt, Frank AU - Leypoldt F AD - 1 Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Universitat de Barcelona, Barcelona, Spain 3 Institute of Clinical Chemistry, Neuroimmunology Unit, University Medical Centre Schleswig-Holstein Campus Lubeck, Germany. FAU - Mannara, Francesco AU - Mannara F AD - 1 Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Universitat de Barcelona, Barcelona, Spain 4 Laboratori de Neurofarmacologia, Facultat de Ciencies de la Salut i de la Vida, Universitat Pompeu Fabra, Barcelona, Spain. FAU - Gutierrez-Cuesta, Javier AU - Gutierrez-Cuesta J AD - 4 Laboratori de Neurofarmacologia, Facultat de Ciencies de la Salut i de la Vida, Universitat Pompeu Fabra, Barcelona, Spain. FAU - Martin-Garcia, Elena AU - Martin-Garcia E AD - 4 Laboratori de Neurofarmacologia, Facultat de Ciencies de la Salut i de la Vida, Universitat Pompeu Fabra, Barcelona, Spain. FAU - Aguilar, Esther AU - Aguilar E AD - 1 Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Universitat de Barcelona, Barcelona, Spain. FAU - Titulaer, Maarten J AU - Titulaer MJ AD - 5 Department of Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands. FAU - Petit-Pedrol, Mar AU - Petit-Pedrol M AD - 1 Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Universitat de Barcelona, Barcelona, Spain. FAU - Jain, Ankit AU - Jain A AD - 6 Department of Neuroscience, University of Pennsylvania, PA, USA. FAU - Balice-Gordon, Rita AU - Balice-Gordon R AD - 6 Department of Neuroscience, University of Pennsylvania, PA, USA. FAU - Lakadamyali, Melike AU - Lakadamyali M AD - 2 ICFO-Institut de Ciencies Fotoniques, Barcelona, Spain. FAU - Graus, Francesc AU - Graus F AD - 1 Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Universitat de Barcelona, Barcelona, Spain 7 Servei de Neurologia, Hospital Clinic, Universitat de Barcelona, Barcelona, Spain. FAU - Maldonado, Rafael AU - Maldonado R AD - 4 Laboratori de Neurofarmacologia, Facultat de Ciencies de la Salut i de la Vida, Universitat Pompeu Fabra, Barcelona, Spain. FAU - Dalmau, Josep AU - Dalmau J AD - 1 Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Universitat de Barcelona, Barcelona, Spain 8 Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA 9 Institucio Catalana de Recerca i Estudis Avancats (ICREA), Barcelona, Spain jdalmau@clinic.ub.es. LA - eng GR - R01 MH094741/MH/NIMH NIH HHS/United States GR - R01 NS077851/NS/NINDS NIH HHS/United States GR - R01MH094741/MH/NIMH NIH HHS/United States GR - R01NS077851/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20141111 PL - England TA - Brain JT - Brain : a journal of neurology JID - 0372537 RN - 0 (Histocompatibility Antigens Class I) RN - 0 (Immunoglobulin G) RN - 0 (MR1 protein, human) RN - 0 (Minor Histocompatibility Antigens) RN - 57-50-1 (Sucrose) SB - IM CIN - Brain. 2015 Jan;138(Pt 1):5-8. PMID: 25564489 MH - Animals MH - Anti-N-Methyl-D-Aspartate Receptor Encephalitis/*cerebrospinal fluid/*immunology MH - Apoptosis/drug effects MH - Behavioral Symptoms/*chemically induced MH - Brain/drug effects/metabolism/pathology MH - Disease Models, Animal MH - Exploratory Behavior/drug effects/physiology MH - Food Preferences/drug effects MH - HEK293 Cells MH - Histocompatibility Antigens Class I/immunology MH - Humans MH - Immunoglobulin G/*adverse effects/cerebrospinal fluid MH - Male MH - Maze Learning/physiology MH - Memory Disorders/*chemically induced MH - Mice MH - Mice, Inbred C57BL MH - Minor Histocompatibility Antigens MH - Sucrose/administration & dosage MH - Swimming/psychology MH - Time Factors PMC - PMC4285189 OTO - NOTNLM OT - animal model OT - anti-NMDAR encephalitis OT - antibodies OT - mechanism OT - pathogenesis EDAT- 2014/11/14 06:00 MHDA- 2015/03/03 06:00 PMCR- 2016/01/01 CRDT- 2014/11/14 06:00 PHST- 2014/11/14 06:00 [entrez] PHST- 2014/11/14 06:00 [pubmed] PHST- 2015/03/03 06:00 [medline] PHST- 2016/01/01 00:00 [pmc-release] AID - awu310 [pii] AID - 10.1093/brain/awu310 [doi] PST - ppublish SO - Brain. 2015 Jan;138(Pt 1):94-109. doi: 10.1093/brain/awu310. Epub 2014 Nov 11.