Human N-methyl D-aspartate receptor antibodies alter memory and behaviour in mice

Planagumà, Jesús; Leypoldt, Frank; Mannara, Francesco; Gutiérrez Cuesta, Javier; Martín García, Elena, 1975-; Aguilar, Esther; Titulaer, Maarten J.; Petit-Pedrol, Mar; Jain, Ankit; Balice-Gordon, Rita; Lakadamyali, Melike; Graus, Francesc; Maldonado, Rafael, 1961-; Dalmau, Josep

Human N-methyl D-aspartate receptor antibodies alter memory and behaviour in mice

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dc.contributor.author Planagumà, Jesúsca
dc.contributor.author Leypoldt, Frankca
dc.contributor.author Mannara, Francescoca
dc.contributor.author Gutiérrez Cuesta, Javierca
dc.contributor.author Martín García, Elena, 1975-ca
dc.contributor.author Aguilar, Estherca
dc.contributor.author Titulaer, Maarten J.ca
dc.contributor.author Petit-Pedrol, Marca
dc.contributor.author Jain, Ankitca
dc.contributor.author Balice-Gordon, Ritaca
dc.contributor.author Lakadamyali, Melikeca
dc.contributor.author Graus, Francescca
dc.contributor.author Maldonado, Rafael, 1961-ca
dc.contributor.author Dalmau, Josepca
dc.date.accessioned 2017-05-03T09:58:46Z
dc.date.available 2017-05-03T09:58:46Z
dc.date.issued 2015
dc.description.abstract 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 µl/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 α-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.
dc.description.sponsorship This work was supported by the National Institutes of Health RO1NS077851 (J.D.), RO1MH094741 (R.B-G. and J.D.), Fundació La Marató de TV3 #101530 (J.D.), Fondo de Investigaciones Sanitarias/Instituto Carlos III (FIS PI11/01780 J.D.), ErasmusMC fellowship (M.T.), and Forschungsförderungsfonds Hamburg-Eppendorf FL)
dc.format.mimetype application/pdfca
dc.identifier.citation Planagumà J, Leypoldt F, Mannara F, Gutiérrez-Cuesta J, Martín-García E, Aguilar E et al. Human N-methyl D-aspartate receptor antibodies alter memory and behaviour in mice. Brain. 2015 Jan;138(Pt 1):94-109. DOI: 10.1093/brain/awu310
dc.identifier.doi http://dx.doi.org/10.1093/brain/awu310
dc.identifier.issn 0006-8950
dc.identifier.uri http://hdl.handle.net/10230/32085
dc.language.iso eng
dc.publisher Oxford University Pressca
dc.relation.ispartof Brain. 2015 Jan;138(Pt 1):94-109
dc.rights © Oxford University Press. This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Brain following peer review. The definitive publisher-authenticated version Planagumà J, Leypoldt F, Mannara F, Gutiérrez-Cuesta J, Martín-García E, Aguilar E et al. Human N-methyl D-aspartate receptor antibodies alter memory and behaviour in mice. Brain. 2015 Jan; 138(Pt 1): 94-109 is available online at: http://dx.doi.org/10.1093/brain/awu310
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.subject.other Sistema nerviós
dc.subject.other Immunoglobulina E
dc.subject.other Trastorns de la memòria
dc.subject.other Conductisme
dc.title Human N-methyl D-aspartate receptor antibodies alter memory and behaviour in miceca
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/acceptedVersion

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