Glycine Receptor Autoantibodies Impair Receptor Function and Induce Motor Dysfunction

Abstract

Objective Impairment of glycinergic neurotransmission leads to complex movement and behavioral disorders. Patients harboring glycine receptor autoantibodies suffer from stiff‐person syndrome or its severe variant progressive encephalomyelitis with rigidity and myoclonus. Enhanced receptor internalization was proposed as the common molecular mechanism upon autoantibody binding. Although functional impairment of glycine receptors following autoantibody binding has recently been investigated, it is still incompletely understood. Methods A cell‐based assay was used for positive sample evaluation. Glycine receptor function was assessed by electrophysiological recordings and radioligand binding assays. The in vivo passive transfer of patient autoantibodies was done using the zebrafish animal model. Results Glycine receptor function as assessed by glycine dose–response curves showed significantly decreased glycine potency in the presence of patient sera. Upon binding of autoantibodies from 2 patients, a decreased fraction of desensitized receptors was observed, whereas closing of the ion channel remained fast. The glycine receptor N‐terminal residues 29A to 62G were mapped as a common epitope of glycine receptor autoantibodies. An in vivo transfer into the zebrafish animal model generated a phenotype with disturbed escape behavior accompanied by a reduced number of glycine receptor clusters in the spinal cord of affected animals. Interpretation Autoantibodies against the extracellular domain mediate alterations of glycine receptor physiology. Moreover, our in vivo data demonstrate that the autoantibodies are a direct cause of the disease, because the transfer of human glycine receptor autoantibodies to zebrafish larvae generated impaired escape behavior in the animal model compatible with abnormal startle response in stiff‐person syndrome or progressive encephalitis with rigidity and myoclonus patients. ANN NEUROL 2020;88:544–561

Autoantibody-associated psychiatric symptoms and syndromes in adults: A narrative review and proposed diagnostic approach

“…There are other criteria involving specific diagnostic measures in these patients that must be met to prove an autoimmune origin of symptoms. Furthermore, many human-to-rodents transfer studies with different human autoantibodies against synaptic proteins such as NMDAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), glutamic acid decarboxylase 65 (GAD65), Glycin or leucine-rich glioma-inactivated 1 (LGI1) derived from patients have demonstrated altered synaptic receptor physiology and its downstream signal cascades leading to impaired synaptic plasticity, brain pathology and abnormalities in behavior, emotional regulation, perception and cognition in rodents ( Rauschenberger et al., 2020 ; Jurek et al., 2019 ; Haselmann et al., 2018 ; Petit Pedrol et al., 2018 ; Planaguma et al., 2015 ; Geis et al., 2012 ). These cause-effect studies in rodents provide a link as to how autoantibodies might trigger psychiatric disease in animals, and depict in analogy to rodent studies a potential basis for autoimmunity in antibody-associated psychiatric syndromes in humans.…”

“…We recommend autoantibody screening in the patient groups we depict (patients need to be given detailed facts and information, and should provide informed consent prior to diagnostic lumbar puncture, see ethical aspects) so that the clinician can decipher the psychiatric syndromes associated with autoantibodies (assuming a potential pathogenic role of these autoantibodies in psychiatric symptomatology). This presumption is based on the aforementioned studies and the known cause-effect human autoantibody-to-rodent transfer investigations ( Rauschenberger et al., 2020 ; Jurek et al., 2019 ; Haselmann et al., 2018 ; Petit Pedrol et al., 2018 ; Planaguma et al., 2015 ; Hansen et al., 2013 ; Geis et al., 2012 ). According to our literature review findings and the above-mentioned associations between psychiatric symptoms and serum autoantibodies, we suggest to screen for antibodies in serum or CSF.…”

“…Another issue is that most of the studies presented only depict an association or correlation between autoantibodies and psychiatric symptoms. Only a few cause-effect studies in rodents exist reporting on the transfer of human autoantibodies to animals ( Rauschenberger et al., 2020 ; Jurek et al., 2019 ; Haselmann et al., 2018 ; Petit Pedrol et al., 2018 ; Planaguma et al., 2015 ; Geis et al., 2012 ) emphasizing the potential pathogenic role of autoantibodies in generating psychiatric symptoms. In addition, note that we do not postulate that psychiatric disorders are autoimmune in nature, but demonstrate evidence that it is worthwhile selecting psychiatric patients for autoantibody screening, and to investigate systematically the role of autoantibodies over a broad range of psychiatric syndromes so that we may better understand the function of autoantibodies in psychiatric disease.…”

Encephalitis with Autoantibodies against the Glutamate Kainate Receptors GluK2

“…This paradigm is similar to the pathogenic mechanisms described in other anti-glutamate receptor encephalitis (NMDAR 9,31 or AMPAR 10,32 ) that are largely mediated by internalization of receptors, whereas for GlyR antibodies a robust antagonistic effect (along with mild to moderate internalization), have been demonstrated. 21,33 Although several autoimmune encephalitis can manifest with cerebellar symptoms, they almost never present as acute cerebellitis. 1 The fact that 4 of 8 patients with GluK2-only or predominant antibodies developed early and prominent clinical or MRI findings of cerebellarbrainstem dysfunction or cerebellitis (causing obstructive hydrocephalus in 2 patients) is notable and provide a clue to suspect this disorder.…”

Spinal Cord Neuronal Network Formation in a 3D Printed Reinforced Matrix—A Model System to Study Disease Mechanisms

“…Disturbances in inhibitory signal transduction processes are associated with different forms of neurological disorders, such as hyperekplexia (OMIM 14 900, startle disease, stiff baby syndrome), stiff person syndrome, epilepsy, pain sensitization, autism, and agoraphobia. [18][19][20][21][22] The underlying molecular and cellular mechanisms in those diseases are not fully understood yet, making a 3D cell culture system a suitable tool to provide better understanding of the disease pathologies.…”