Human N-methyl D-aspartate receptor antibodies alter memory and behaviour in mice.
Brain. 2014-11-11; 138(1): 94-109
DOI: 10.1093/brain/awu310
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Planagumà J(1), Leypoldt F(2), Mannara F(3), Gutiérrez-Cuesta J(4), Martín-García
E(4), Aguilar E(5), Titulaer MJ(6), Petit-Pedrol M(5), Jain A(7), Balice-Gordon
R(7), Lakadamyali M(8), Graus F(9), Maldonado R(4), Dalmau J(10).
Author information:
(1)1 Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital
Clínic, Universitat de Barcelona, Barcelona, Spain 2 ICFO-Institut de Ciències
Fotòniques, Barcelona, Spain.
(2)1 Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital
Clínic, Universitat de Barcelona, Barcelona, Spain 3 Institute of Clinical
Chemistry, Neuroimmunology Unit, University Medical Centre Schleswig-Holstein
Campus Lübeck, Germany.
(3)1 Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital
Clínic, Universitat de Barcelona, Barcelona, Spain 4 Laboratori de
Neurofarmacologia, Facultat de Ciències de la Salut i de la Vida, Universitat
Pompeu Fabra, Barcelona, Spain.
(4)4 Laboratori de Neurofarmacologia, Facultat de Ciències de la Salut i de la
Vida, Universitat Pompeu Fabra, Barcelona, Spain.
(5)1 Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital
Clínic, Universitat de Barcelona, Barcelona, Spain.
(6)5 Department of Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands.
(7)6 Department of Neuroscience, University of Pennsylvania, PA, USA.
(8)2 ICFO-Institut de Ciències Fotòniques, Barcelona, Spain.
(9)1 Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital
Clínic, Universitat de Barcelona, Barcelona, Spain 7 Servei de Neurologia,
Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.
(10)1 Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS),
Hospital Clínic, Universitat de Barcelona, Barcelona, Spain 8 Department of
Neurology, University of Pennsylvania, Philadelphia, PA, USA 9 Institució
Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
.
Comment in
Brain. 2015 Jan;138(Pt 1):5-8.
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.
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