Human gestational N-methyl-d-aspartate receptor autoantibodies impair neonatal murine brain function

doi:10.1002/ana.25552

. 2019 Nov;86(5):656-670.

doi: 10.1002/ana.25552. Epub 2019 Sep 18.

Human gestational N-methyl-d-aspartate receptor autoantibodies impair neonatal murine brain function

Betty Jurek^{1

2}, Mariya Chayka^{1

2}, Jakob Kreye^{1

2}, Katharina Lang^{1

2}, Larissa Kraus^{1

3

4}, Pawel Fidzinski^{1

3}, Hans-Christian Kornau^{2

5}, Le-Minh Dao^{1

2}, Nina K Wenke², Melissa Long⁶, Marion Rivalan⁶, York Winter⁶, Jonas Leubner¹, Julia Herken¹, Simone Mayer⁷, Susanne Mueller^{1

8

9}, Philipp Boehm-Sturm^{1

8

9}, Ulrich Dirnagl^{1

2

9}, Dietmar Schmitz^{2

5

10}, Michael Kölch¹¹, Harald Prüss^{1

2

12}

Affiliations

¹ Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
² German Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, Germany.
³ Clinical and Experimental Epileptology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁴ Berlin Institute of Health, Berlin, Germany.
⁵ Neuroscience Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁶ Neurocure Cluster of Excellence, Animal Outcome Core Facility, Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁷ Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research and Department of Neurology, University of California, San Francisco, San Francisco, CA.
⁸ Neurocure Cluster of Excellence, Core Facility 7T Experimental MRIs, Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁹ Center for Stroke Research, Charité-Universitätsmedizin Berlin, Berlin, Germany.
¹⁰ Einstein Center for Neurosciences, Berlin, Germany.
¹¹ Department for Child and Adolescent Psychiatry, Neurology, Psychosomatics, and Psychotherapy, Universitätsmedizin Rostock, Rostock, Germany.
¹² Department of Neurology, Center for Autoimmune Encephalitis and Paraneoplastic Neurological Syndromes, Charité-Universitätsmedizin Berlin, Berlin, Germany.

PMID: 31325344
DOI: 10.1002/ana.25552

Human gestational N-methyl-d-aspartate receptor autoantibodies impair neonatal murine brain function

Betty Jurek et al. Ann Neurol. 2019 Nov.

. 2019 Nov;86(5):656-670.

doi: 10.1002/ana.25552. Epub 2019 Sep 18.

Authors

Affiliations

¹ Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
² German Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, Germany.
³ Clinical and Experimental Epileptology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁴ Berlin Institute of Health, Berlin, Germany.
⁵ Neuroscience Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁶ Neurocure Cluster of Excellence, Animal Outcome Core Facility, Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁷ Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research and Department of Neurology, University of California, San Francisco, San Francisco, CA.
⁸ Neurocure Cluster of Excellence, Core Facility 7T Experimental MRIs, Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁹ Center for Stroke Research, Charité-Universitätsmedizin Berlin, Berlin, Germany.
¹⁰ Einstein Center for Neurosciences, Berlin, Germany.
¹¹ Department for Child and Adolescent Psychiatry, Neurology, Psychosomatics, and Psychotherapy, Universitätsmedizin Rostock, Rostock, Germany.
¹² Department of Neurology, Center for Autoimmune Encephalitis and Paraneoplastic Neurological Syndromes, Charité-Universitätsmedizin Berlin, Berlin, Germany.

PMID: 31325344
DOI: 10.1002/ana.25552

Abstract

Objective: Maternal autoantibodies are a risk factor for impaired brain development in offspring. Antibodies (ABs) against the NR1 (GluN1) subunit of the N-methyl-d-aspartate receptor (NMDAR) are among the most frequently diagnosed anti-neuronal surface ABs, yet little is known about effects on fetal development during pregnancy.

Methods: We established a murine model of in utero exposure to human recombinant NR1 and isotype-matched nonreactive control ABs. Pregnant C57BL/6J mice were intraperitoneally injected on embryonic days 13 and 17 each with 240μg of human monoclonal ABs. Offspring were investigated for acute and chronic effects on NMDAR function, brain development, and behavior.

Results: Transferred NR1 ABs enriched in the fetus and bound to synaptic structures in the fetal brain. Density of NMDAR was considerably reduced (up to -49.2%) and electrophysiological properties were altered, reflected by decreased amplitudes of spontaneous excitatory postsynaptic currents in young neonates (-34.4%). NR1 AB-treated animals displayed increased early postnatal mortality (+27.2%), impaired neurodevelopmental reflexes, altered blood pH, and reduced bodyweight. During adolescence and adulthood, animals showed hyperactivity (+27.8% median activity over 14 days), lower anxiety, and impaired sensorimotor gating. NR1 ABs caused long-lasting neuropathological effects also in aged mice (10 months), such as reduced volumes of cerebellum, midbrain, and brainstem.

Interpretation: The data collectively support a model in which asymptomatic mothers can harbor low-level pathogenic human NR1 ABs that are diaplacentally transferred, causing neurotoxic effects on neonatal development. Thus, AB-mediated network changes may represent a potentially treatable neurodevelopmental congenital brain disorder contributing to lifelong neuropsychiatric morbidity in affected children. ANN NEUROL 2019;86:656-670.

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Comment in

Do maternal anti-N-methyl-D-aspartate receptor antibodies promote development of neuropsychiatric disease in children?
Pröbstel AK, Zamvil SS. Pröbstel AK, et al. Ann Neurol. 2019 Nov;86(5):653-655. doi: 10.1002/ana.25584. Epub 2019 Sep 18. Ann Neurol. 2019. PMID: 31531881 Free PMC article. No abstract available.
Reply to "Pregnancy, N-Methyl-D-Aspartate Receptor Antibodies, and Neuropsychiatric Diseases".
Jurek B, Chayka M, Kreye J, Koelch M, Prüss H. Jurek B, et al. Ann Neurol. 2020 Feb;87(2):325-326. doi: 10.1002/ana.25653. Epub 2019 Dec 10. Ann Neurol. 2020. PMID: 31782158 No abstract available.
Pregnancy, N-Methyl-D-Aspartate Receptor Antibodies, and Neuropsychiatric Diseases.
Dalmau J. Dalmau J. Ann Neurol. 2020 Feb;87(2):324-325. doi: 10.1002/ana.25654. Epub 2019 Dec 10. Ann Neurol. 2020. PMID: 31782163 No abstract available.

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References

1. Kowal C, Athanassiou A, Chen H, Diamond B. Maternal antibodies and developing blood-brain barrier. Immunol Res 2015;63:18-25.
1. Palmeira P, Quinello C, Silveira-Lessa AL, et al. IgG placental transfer in healthy and pathological pregnancies. Clin Dev Immunol 2012;2012:985646.
1. Kumar MA, Jain A, Dechant VE, et al. Anti-N-methyl-D-aspartate receptor encephalitis during pregnancy. Arch Neurol 2010;67:884-887.
1. Estes ML, McAllister AK. Maternal immune activation: implications for neuropsychiatric disorders. Science 2016;353:772-777.
1. Fox E, Amaral D, Van de Water J. Maternal and fetal antibrain antibodies in development and disease. Dev Neurobiol 2012;72:1327-1334.

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[1] Kowal C, Athanassiou A, Chen H, Diamond B. Maternal antibodies and developing blood-brain barrier. Immunol Res 2015;63:18-25.

[2] Kowal C, Athanassiou A, Chen H, Diamond B. Maternal antibodies and developing blood-brain barrier. Immunol Res 2015;63:18-25.

[3] Palmeira P, Quinello C, Silveira-Lessa AL, et al. IgG placental transfer in healthy and pathological pregnancies. Clin Dev Immunol 2012;2012:985646.

[4] Palmeira P, Quinello C, Silveira-Lessa AL, et al. IgG placental transfer in healthy and pathological pregnancies. Clin Dev Immunol 2012;2012:985646.

[5] Kumar MA, Jain A, Dechant VE, et al. Anti-N-methyl-D-aspartate receptor encephalitis during pregnancy. Arch Neurol 2010;67:884-887.

[6] Kumar MA, Jain A, Dechant VE, et al. Anti-N-methyl-D-aspartate receptor encephalitis during pregnancy. Arch Neurol 2010;67:884-887.

[7] Estes ML, McAllister AK. Maternal immune activation: implications for neuropsychiatric disorders. Science 2016;353:772-777.

[8] Estes ML, McAllister AK. Maternal immune activation: implications for neuropsychiatric disorders. Science 2016;353:772-777.

[9] Fox E, Amaral D, Van de Water J. Maternal and fetal antibrain antibodies in development and disease. Dev Neurobiol 2012;72:1327-1334.

[10] Fox E, Amaral D, Van de Water J. Maternal and fetal antibrain antibodies in development and disease. Dev Neurobiol 2012;72:1327-1334.

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Human gestational N-methyl-d-aspartate receptor autoantibodies impair neonatal murine brain function

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Human gestational N-methyl-d-aspartate receptor autoantibodies impair neonatal murine brain function

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