Journal Article

DZNE-2023-00460

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Microglia actively remove NR1 autoantibody-bound NMDA receptors and associated post-synaptic proteins in neuron microglia co-cultures.

Rahman, K. A. ; Orlando, M. ; Boulos, A. ; Andrzejak, E.DZNE* ; Schmitz, D.DZNE* ; Ziv, N. E. ; Prüss, H.DZNE* ; Garner, C. C.DZNE* ; Ichkova, A. (Last author)DZNE*

2023
Wiley-Liss Bognor Regis [u.a.]

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Please use a persistent id in citations: doi:10.1002/glia.24369

Abstract: Autoantibodies against the NR1 subunit of NMDA receptors (NMDARs) have been shown to promote crosslinking and internalization of bound receptors in NMDAR encephalitis (NMDARE). This internalization-mediated loss of NMDARs is thought to be the major mechanism leading to pathogenic outcomes in patients. However, the role of bound autoantibody in engaging the resident immune cells, microglia, remains poorly understood. Here, using a patient-derived monoclonal NR1 autoantibody (hNR1-mAb) and a co-culture system of microglia and neurons, we could show that hNR1-mAb bound to hippocampal neurons led to microglia-mediated removal of hNR1-mAb bound NMDARs. These complexes were found to accumulate inside endo-lysosomal compartments of microglia. Utilizing another patient isolated monoclonal autoantibody, against the α1-subunit of GABAA receptors (α1-GABAA -mAb), such removal of receptors was found to be specific to the antibody-bound receptor targets. Interestingly, along with receptor removal, we also observed a reduction in synapse number, more specifically in the numbers of post-synaptic proteins like PSD95 and Homer 1, when microglia were present in the culture. Importantly, mutations in the Fc region of hNR1-mAb, blocking its Fcγ receptor (FcγR) and complement binding, attenuated hNR1-mAb driven loss of NMDARs and synapses, indicating that microglia engagement by bound hNR1-mAb is critical for receptor and synapse loss. Our data argues for an active involvement of microglia in removal of NMDARs and other receptors in individuals with autoimmune encephalitis, thereby contributing to the etiology of these diseases.

Keyword(s): Humans (MeSH) ; Receptors, N-Methyl-D-Aspartate: genetics (MeSH) ; Receptors, N-Methyl-D-Aspartate: metabolism (MeSH) ; Autoantibodies: metabolism (MeSH) ; Coculture Techniques (MeSH) ; Microglia: metabolism (MeSH) ; Neurons: metabolism (MeSH) ; gamma-Aminobutyric Acid: metabolism (MeSH) ; co-culture ; NMDAR ; antibody mediated autoimmune encephalitis ; autoantibodies ; microglia, hippocampal neurons, co-culture, pre-labeling ; hippocampal neurons ; microglia ; pre-labeling ; Receptors, N-Methyl-D-Aspartate ; Autoantibodies ; gamma-Aminobutyric Acid

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Contributing Institute(s):

1. Synaptopathy (AG Garner)
2. Network Dysfunction (AG Schmitz 1 ; AG Schmitz)
3. Autoimmune Enzephalopathies (AG Prüß)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)
2. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2023

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Wiley ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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