GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation: a potential neurogenetic pathway to panic disorder

Deckert, Jürgen; Weber, Heike; Villmann, Carmen; Lonsdorf, Tina B.; Richter, Jan; Andreatta, Marta; Vasquez, Alejandro Arias; Hommers, Leif; Kent, Lindsey; Schartner, Christoph; Cichon, Sven; Wolf, Christiane; Schaefer, Natascha; Collenberg, Cora R. von; Wachter, Britta; Blum, Robert; Schümann, Dirk; Scharfenort, Robert; Schumacher, Johannes; Aj, Forstner; Baumann, Christian; Schiele, Miriam A.; Notzon, Swantje; Zwanzger, Peter; Janzing, J.G.E.; Galesloot, Tessel E.; Kiemeney, Lambertus A.; Gajewska, Agnieszka; Glotzbach-Schoon, Evelyn; Mühlberger, Andreas; Alpers, Georg W.; Fydrich, Thomas; Fehm, Lydia; Gerlach, Alexander L.; Kircher, Tilo; Lang, Thomas; Ströhle, Andreas; Arolt, Volker; Wittchen, Hans‐Ulrich; Kalisch, Raffaël; Büchel, Christian; Hamm, Alfons O.; Nöthen, Markus M.; Romanos, Marcel; Domschke, Katharina; Pauli, Paul; Reif, Andreas

doi:10.1038/mp.2017.2

Cited by 51 publications

(49 citation statements)

References 71 publications

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“…The time window of 1‐hour preincubation with the patient GlyR autoantibodies is accompanied by an internalization rate of 30% of surface GlyRs (data not shown). A reduction by 30% of cell surface receptors usually does not change maximal current amplitudes as demonstrated by whole‐cell recordings from cells transfected with GlyRα1 mutants associated with hyperekplexia 32 . No significant changes in whole‐cell maximum currents were found following application of a saturating glycine concentration (1mM; see Fig 2D).…”

Section: Resultsmentioning

confidence: 81%

“…One‐hour incubation with the GlyR autoantibody resulted in receptor internalization of about 30 to 50% 4 . Current knowledge from GlyRα1 mutant receptors associated with hyperekplexia 32 revealed that a reduction by 30 to 50% of cell surface receptor protein does usually not change maximal current amplitudes. If, however, the GlyR protein is reduced by >85%, a decrease in glycine‐gated chloride current amplitudes at maximal glycine concentrations would be expected 33,45,46 .…”

Section: Discussionmentioning

confidence: 99%

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Glycine Receptor Autoantibodies Impair Receptor Function and Induce Motor Dysfunction

Rauschenberger

Wardenburg

Schaefer

et al. 2020

Annals of Neurology

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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

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Section: Resultsmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Glycine Receptor Autoantibodies Impair Receptor Function and Induce Motor Dysfunction

Rauschenberger

Wardenburg

Schaefer

et al. 2020

Annals of Neurology

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“…Eighty‐one participants were selected from a larger sample of healthy volunteers recruited within the framework of the collaborative research center SFB TRR58 (Deckert et al, ; Schartner et al, ; Schiele et al, ). BDNF rs6265 was genotyped using standard PCR followed by enzymatic digestion and staining according to our previously published protocol (Mühlberger et al, ).…”

Section: Methodsmentioning

confidence: 99%

Human BDNF rs6265 polymorphism as a mediator for the generalization of contextual anxiety

Andreatta

Neueder

Genheimer

et al. 2018

J of Neuroscience Research

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The Met allele of the human brain-derived neurotrophic factor (BDNF) gene might be a risk factor for anxiety disorders and is associated with reduced hippocampal volume. Notably, hippocampus plays a crucial role in contextual learning and generalization. The role of the BDNF gene variation in human context-conditioning and generalization is still unknown. We investigated 33 carriers of the Met allele (18 females) and 32 homozygous carriers of the Val allele (15 females) with a virtual-reality context-conditioning paradigm. Electric stimulations (unconditioned stimulus, US)were unpredictably delivered in one virtual office (CTX+), but never in another virtual office (CTX-). During generalization, participants revisited CTX+ and CTX-and a generalization office (G-CTX), which was a mix of the other two. Rating data indicated successful conditioning (more negative valence, higher arousal, anxiety and contingency ratings for CTX+ than CTX-), and generalization of conditioned anxiety by comparable ratings for G-CTX and CTX+. The startle data indicated discriminative learning for Met allele carriers, but not for Val homozygotes. Moreover, a trend effect suggests that startle responses of only the Met carriers were slightly potentiated in G-CTX versus CTX-. In sum, the BDNF polymorphism did not affect contextual learning and its generalization on a verbal level. However, the physiological data suggest that Met carriers are characterized by fast discriminative contextual learning and a tendency to generalize anxiety responses to ambiguous contexts. We propose that such learning may be related to reduced hippocampal functionality and the basis for the risk of Met carriers to develop anxiety disorders. K E Y W O R D SBDNF, conditioned anxiety, context conditioning, generalization processes, startle response | 301 ANDREATTA et Al.

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“…Mutations in the genes encoding this GlyR subtype ( GLRA1 and GLRB ) cause startle disease, characterized by noise- or touch-induced non-epileptic seizures, excessive muscle stiffness and neonatal apnea episodes in cattle, mice and humans (Harvey et al, 2008; Bode and Lynch, 2014). Allelic variants of GLRB have also recently been associated with agoraphobic behavior, an increased startle response and fear network activation (Deckert et al, 2017). …”

Section: Introductionmentioning

confidence: 99%

Structure-Function Analysis of the GlyR α2 Subunit Autism Mutation p.R323L Reveals a Gain-of-Function

Zhang

Harvey³

et al. 2017

Front. Mol. Neurosci.

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Glycine receptors (GlyRs) containing the α2 subunit regulate cortical interneuron migration. Disruption of the GlyR α2 subunit gene (Glra2) in mice leads to disrupted dorsal cortical progenitor homeostasis, leading to a depletion of projection neurons and moderate microcephaly in newborn mice. In humans, rare variants in GLRA2, which is located on the X chromosome, are associated with autism spectrum disorder (ASD) in the hemizygous state in males. These include a microdeletion (GLRA2∆ex8-9) and missense mutations in GLRA2 (p.N109S and p.R126Q) that impair cell-surface expression of GlyR α2, and either abolish or markedly reduce sensitivity to glycine. We report the functional characterization of a third missense variant in GLRA2 (p.R323L), associated with autism, macrocephaly, epilepsy and hypothyroidism in a female proband. Using heterosynapse and macroscopic current recording techniques, we reveal that GlyR α2R323L exhibits reduced glycine sensitivity, but significantly increased inhibitory postsynaptic current (IPSC) rise and decay times. Site-directed mutagenesis revealed that the nature of the amino acid switch at position 323 is critical for impairment of GlyR function. Single-channel recordings revealed that the conductance of α2R323Lβ channels was higher than α2β channels. Longer mean opening durations induced by p.R323L may be due to a change in the gating pathway that enhances the stability of the GlyR open state. The slower synaptic decay times, longer duration active periods and increase in conductance demonstrates that the GlyR α2 p.R323L mutation results in an overall gain of function, and that GlyR α2 mutations can be pathogenic in the heterozygous state in females.

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GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation: a potential neurogenetic pathway to panic disorder

Cited by 51 publications

References 71 publications

Glycine Receptor Autoantibodies Impair Receptor Function and Induce Motor Dysfunction

Glycine Receptor Autoantibodies Impair Receptor Function and Induce Motor Dysfunction

Human BDNF rs6265 polymorphism as a mediator for the generalization of contextual anxiety

Structure-Function Analysis of the GlyR α2 Subunit Autism Mutation p.R323L Reveals a Gain-of-Function

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