Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Jan 5;10(1):77.
doi: 10.3390/cells10010077.

NMDA and AMPA Receptor Autoantibodies in Brain Disorders: From Molecular Mechanisms to Clinical Features

Fabrizio Gardoni  1 , Jennifer Stanic  1 , Diego Scheggia  1 , Alberto Benussi  2 , Barbara Borroni  2 , Monica Di Luca  1
Affiliations
Review

NMDA and AMPA Receptor Autoantibodies in Brain Disorders: From Molecular Mechanisms to Clinical Features

Fabrizio Gardoni et al. Cells. .

Abstract

The role of autoimmunity in central nervous system (CNS) disorders is rapidly expanding. In the last twenty years, different types of autoantibodies targeting subunits of ionotropic glutamate receptors have been found in a variety of patients affected by brain disorders. Several of these antibodies are directed against NMDA receptors (NMDAR), mostly in autoimmune encephalitis, whereas a growing field of research has identified antibodies against AMPA receptor (AMPAR) subunits in patients with different types of epilepsy or frontotemporal dementia. Several in vitro and in vivo studies performed in the last decade have dramatically improved our understanding of the molecular and functional effects induced by both NMDAR and AMPAR autoantibodies at the excitatory glutamatergic synapse and, consequently, their possible role in the onset of clinical symptoms. In particular, the method by which autoantibodies can modulate the localization at synapses of specific target subunits leading to functional impairments and behavioral alterations has been well addressed in animal studies. Overall, these preclinical studies have opened new avenues for the development of novel pharmacological treatments specifically targeting the synaptic activation of ionotropic glutamate receptors.

Keywords: autoimmunity; brain disorders; excitatory synapse; glutamate.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Graphic representation of molecular and cellular mechanisms triggered by anti-GluN1 antibodies through interaction with synaptic or extrasynaptic NMDARs.
Figure 2
Figure 2
Graphic representation of molecular and cellular mechanisms triggered by anti-GluA3 antibodies.
See this image and copyright information in PMC

References

    1. Palese F., Bonomi E., Nuzzo T., Benussi A., Mellone M., Zianni E., Cisani F., Casamassa A., Alberici A., Scheggia D., et al. Anti-GluA3 antibodies in frontotemporal dementia: Effects on glutamatergic neurotransmission and synaptic failure. Neurobiol. Aging. 2020;86:143–155. - PubMed
    1. Panzer J.A., Gleichman A.J., Lynch D.R. Glutamatergic autoencephalitides: An emerging field. J. Neural Transm. 2014;121:957–968. doi: 10.1007/s00702-013-1152-4. - DOI - PMC - PubMed
    1. Kayser M.S., Dalmau J. Anti-NMDA receptor encephalitis, autoimmunity, and psychosis. Schizophr. Res. 2016;176:36–40. doi: 10.1016/j.schres.2014.10.007. - DOI - PMC - PubMed
    1. Levite M. Glutamate receptor antibodies in neurological diseases: Anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 anti-bodies, anti-NMDA-NR2A/B antibodies, anti-mGluR1 antibodies or anti-mGluR5 antibodies are present in subpopulations of patients with either: Epilepsy, encephalitis, cerebellar ataxia, systemic lupus erythematosus (SLE) and neuropsychiatric SLE, Sjogren’s syndrome, schizophrenia, mania or stroke. These autoimmune anti-glutamate receptor antibodies can bind neurons in few brain regions, activate glutamate receptors, decrease glutamate receptor’s expression, impair gluta-mate-induced signaling and function, activate blood brain barrier endothelial cells, kill neurons, damage the brain, induce behavioral/psychiatric/cognitive abnormalities and ataxia in animal models, and can be removed or silenced in some pa-tients by immunotherapy. J. Neural Transm. 2014;121:1029–1075. - PubMed
    1. Hunter D., Jamet Z., Groc L. Autoimmunity and NMDA receptor in brain disorders: Where do we stand? Neurobiol. Dis. 2021;147:105161. doi: 10.1016/j.nbd.2020.105161. - DOI - PubMed

MeSH terms