TY  - JOUR
A1  - Rauschenberger, Vera
A1  - von Wardenburg, Niels
A1  - Schaefer, Natascha
A1  - Ogino, Kazutoyo
A1  - Hirata, Hiromi
A1  - Lillesaar, Christina
A1  - Kluck, Christoph J.
A1  - Meinck, Hans‐Michael
A1  - Borrmann, Marc
A1  - Weishaupt, Andreas
A1  - Doppler, Kathrin
A1  - Wickel, Jonathan
A1  - Geis, Christian
A1  - Sommer, Claudia
A1  - Villmann, Carmen
T1  - Glycine Receptor Autoantibodies Impair Receptor Function and Induce Motor Dysfunction
JF  - Annals of Neurology
N2  - 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 \(^{29}\)A to \(^{62}\)G 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.
KW  - glycine receptor autoantibodies
KW  - behavioral disorders
KW  - neurology
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-216005
VL  - 88
IS  - 3
SP  - 544
EP  - 561
ER  - 
TY  - JOUR
A1  - Schaefer, Natascha
A1  - Signoret-Genest, Jérémy
A1  - von Collenberg, Cora R.
A1  - Wachter, Britta
A1  - Deckert, Jürgen
A1  - Tovote, Philip
A1  - Blum, Robert
A1  - Villmann, Carmen
T1  - Anxiety and Startle Phenotypes in Glrb Spastic and Glra1 Spasmodic Mouse Mutants
JF  - Frontiers in Molecular Neuroscience
N2  - A GWAS study recently demonstrated single nucleotide polymorphisms (SNPs) in the human GLRB gene of individuals with a prevalence for agoraphobia. GLRB encodes the glycine receptor (GlyRs) β subunit. The identified SNPs are localized within the gene flanking regions (3′ and 5′ UTRs) and intronic regions. It was suggested that these nucleotide polymorphisms modify GlyRs expression and phenotypic behavior in humans contributing to an anxiety phenotype as a mild form of hyperekplexia. Hyperekplexia is a human neuromotor disorder with massive startle phenotypes due to mutations in genes encoding GlyRs subunits. GLRA1 mutations have been more commonly observed than GLRB mutations. If an anxiety phenotype contributes to the hyperekplexia disease pattern has not been investigated yet. Here, we compared two mouse models harboring either a mutation in the murine Glra1 or Glrb gene with regard to anxiety and startle phenotypes. Homozygous spasmodic animals carrying a Glra1 point mutation (alanine 52 to serine) displayed abnormally enhanced startle responses. Moreover, spasmodic mice exhibited significant changes in fear-related behaviors (freezing, rearing and time spent on back) analyzed during the startle paradigm, even in a neutral context. Spastic mice exhibit reduced expression levels of the full-length GlyRs β subunit due to aberrant splicing of the Glrb gene. Heterozygous animals appear normal without an obvious behavioral phenotype and thus might reflect the human situation analyzed in the GWAS study on agoraphobia and startle. In contrast to spasmodic mice, heterozygous spastic animals revealed no startle phenotype in a neutral as well as a conditioning context. Other mechanisms such as a modulatory function of the GlyRs β subunit within glycinergic circuits in neuronal networks important for fear and fear-related behavior may exist. Possibly, in human additional changes in fear and fear-related circuits either due to gene-gene interactions e.g., with GLRA1 genes or epigenetic factors are necessary to create the agoraphobia and in particular the startle phenotype.
KW  - glycine receptor
KW  - spastic
KW  - fear
KW  - anxiety
KW  - startle reaction
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-210041
SN  - 1662-5099
VL  - 13
IS  - 152
ER  -