14050
2011
eng
e16775
2
6
article
1
2016-11-17
--
--
Human Stiff-Person Syndrome IgG Induces Anxious Behavior in Rats
Background:
Anxiety is a heterogeneous behavioral domain playing a role in a variety of neuropsychiatric diseases. While anxiety is the cardinal symptom in disorders such as panic disorder, co-morbid anxious behavior can occur in a variety of diseases. Stiff person syndrome (SPS) is a CNS disorder characterized by increased muscle tone and prominent agoraphobia and anxiety. Most patients have high-titer antibodies against glutamate decarboxylase (GAD) 65. The pathogenic role of these autoantibodies is unclear.
Methodology/Principal Findings:
We re-investigated a 53 year old woman with SPS and profound anxiety for GABA-A receptor binding in the amygdala with (11) C-flumazenil PET scan and studied the potential pathogenic role of purified IgG from her plasma filtrates containing high-titer antibodies against GAD 65. We passively transferred the IgG fraction intrathecally into rats and analyzed the effects using behavioral and in vivo electrophysiological methods. In cell culture, we measured the effect of patient IgG on GABA release from hippocampal neurons. Repetitive intrathecal application of purified patient IgG in rats resulted in an anxious phenotype resembling the core symptoms of the patient. Patient IgG selectively bound to rat amygdala, hippocampus, and frontal cortical areas. In cultured rat hippocampal neurons, patient IgG inhibited GABA release. In line with these experimental results, the GABA-A receptor binding potential was reduced in the patient's amygdala/hippocampus complex. No motor abnormalities were found in recipient rats.
Conclusion/Significance:
The observations in rats after passive transfer lead us to propose that anxiety-like behavior can be induced in rats by passive transfer of IgG from a SPS patient positive for anti-GAD 65 antibodies. Anxiety, in this case, thus may be an antibody-mediated phenomenon with consecutive disturbance of GABAergic signaling in the amygdala region.
Plos One
10.1371/journal.pone.0016775
urn:nbn:de:bvb:20-opus-140506
PLoS ONE 6(2):e16775. doi:10.1371/journal.pone.0016775
Christian Geis
Andreas Weishaupt
Benedikt Grünewald
Thomas Wultsch
Andreas Reif
Manfred Gerlach
Ron Dirkx
Michele Solimena
Klaus V Toyka
Franco Folli
Daniela Perani
Manfred Heckmann
Claudia Sommer
eng
uncontrolled
Glutamic-acid decarboxylase anxiety
eng
uncontrolled
spinal-cord-injury
eng
uncontrolled
presynaptic inhibition
eng
uncontrolled
65-kda isoform
eng
uncontrolled
fear memory
eng
uncontrolled
antibodies
eng
uncontrolled
disorder
eng
uncontrolled
neurons
eng
uncontrolled
anxiety
eng
uncontrolled
autoantibodies
Medizin und Gesundheit
open_access
Neurologische Klinik und Poliklinik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/14050/067_Geis_PLOS-ONE.PDF
6351
2011
eng
article
1
2013-01-11
--
--
Human Stiff-Person Syndrome IgG Induces Anxious Behavior in Rats
Background: Anxiety is a heterogeneous behavioral domain playing a role in a variety of neuropsychiatric diseases. While anxiety is the cardinal symptom in disorders such as panic disorder, co-morbid anxious behavior can occur in a variety of diseases. Stiff person syndrome (SPS) is a CNS disorder characterized by increased muscle tone and prominent agoraphobia and anxiety. Most patients have high-titer antibodies against glutamate decarboxylase (GAD) 65. The pathogenic role of these autoantibodies is unclear. Methodology/Principal Findings: We re-investigated a 53 year old woman with SPS and profound anxiety for GABA-A receptor binding in the amygdala with (11)C-flumazenil PET scan and studied the potential pathogenic role of purified IgG from her plasma filtrates containing high-titer antibodies against GAD 65. We passively transferred the IgG fraction intrathecally into rats and analyzed the effects using behavioral and in vivo electrophysiological methods. In cell culture, we measured the effect of patient IgG on GABA release from hippocampal neurons. Repetitive intrathecal application of purified patient IgG in rats resulted in an anxious phenotype resembling the core symptoms of the patient. Patient IgG selectively bound to rat amygdala, hippocampus, and frontal cortical areas. In cultured rat hippocampal neurons, patient IgG inhibited GABA release. In line with these experimental results, the GABA-A receptor binding potential was reduced in the patient’s amygdala/hippocampus complex. No motor abnormalities were found in recipient rats. Conclusion/Significance: The observations in rats after passive transfer lead us to propose that anxiety-like behavior can be induced in rats by passive transfer of IgG from a SPS patient positive for anti-GAD 65 antibodies. Anxiety, in this case, thus may be an antibody-mediated phenomenon with consecutive disturbance of GABAergic signaling in the amygdala region.
urn:nbn:de:bvb:20-opus-74757
7475
In: PLOS ONE (2011) 6:2, 10.1371/journal.pone.0016775
Christian Geis
Andreas Weishaupt
Benedikt Grünewald
Thomas Wultsch
Andreas Reif
Manfred Gerlach
Ron Dirkx
Michele Solimena
Daniela Perani
Manfred Heckmann
Klaus V. Toyka
Franco Folli
Claudia Sommer
deu
swd
Medizin
Medizin und Gesundheit
open_access
Neurologische Klinik und Poliklinik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/6351/Geis_journal.pone.0016775.pdf
21600
2020
eng
544
561
3
88
article
1
--
--
--
Glycine Receptor Autoantibodies Impair Receptor Function and Induce Motor Dysfunction
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.
Annals of Neurology
10.1002/ana.25832
urn:nbn:de:bvb:20-opus-216005
2020-11-09T13:00:41+00:00
sword
swordwue
attachment; filename=deposit.zip
18850d8a4dc7a44d0ef5067395525605
Annals of Neurology 2020, 88(3):544–561. DOI: 10.1002/ana.25832
false
true
CC BY-NC: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell 4.0 International
Vera Rauschenberger
Niels von Wardenburg
Natascha Schaefer
Kazutoyo Ogino
Hiromi Hirata
Christina Lillesaar
Christoph J. Kluck
Hans‐Michael Meinck
Marc Borrmann
Andreas Weishaupt
Kathrin Doppler
Jonathan Wickel
Christian Geis
Claudia Sommer
Carmen Villmann
eng
uncontrolled
glycine receptor autoantibodies
eng
uncontrolled
behavioral disorders
eng
uncontrolled
neurology
Medizin und Gesundheit
open_access
Institut für Klinische Neurobiologie
Neurologische Klinik und Poliklinik
Import
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/21600/ANA_ANA25832.pdf
16600
2016
eng
1407
9
17
article
1
2018-07-27
--
--
Efficacy of Polyvalent Human Immunoglobulins in an Animal Model of Neuromyelitis Optica Evoked by Intrathecal Anti-Aquaporin 4 Antibodies
Neuromyelitis Optica Spectrum Disorders (NMOSD) are associated with autoantibodies (ABs) targeting the astrocytic aquaporin-4 water channels (AQP4-ABs). These ABs have a direct pathogenic role by initiating a variety of immunological and inflammatory processes in the course of disease. In a recently-established animal model, chronic intrathecal passive-transfer of immunoglobulin G from NMOSD patients (NMO-IgG), or of recombinant human AQP4-ABs (rAB-AQP4), provided evidence for complementary and immune-cell independent effects of AQP4-ABs. Utilizing this animal model, we here tested the effects of systemically and intrathecally applied pooled human immunoglobulins (IVIg) using a preventive and a therapeutic paradigm. In NMO-IgG animals, prophylactic application of systemic IVIg led to a reduced median disease score of 2.4 on a 0–10 scale, in comparison to 4.1 with sham treatment. Therapeutic IVIg, applied systemically after the 10th intrathecal NMO-IgG injection, significantly reduced the disease score by 0.8. Intrathecal IVIg application induced a beneficial effect in animals with NMO-IgG (median score IVIg 1.6 vs. sham 3.7) or with rAB-AQP4 (median score IVIg 2.0 vs. sham 3.7). We here provide evidence that treatment with IVIg ameliorates disease symptoms in this passive-transfer model, in analogy to former studies investigating passive-transfer animal models of other antibody-mediated disorders.
International Journal of Molecular Sciences
10.3390/ijms17091407
urn:nbn:de:bvb:20-opus-166000
International Journal of Molecular Sciences 2016, 17, 1407; doi:10.3390/ijms17091407
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Benedikt Grünewald
Jeffrey L. Bennett
Klaus V. Toyka
Claudia Sommer
Christian Geis
eng
uncontrolled
intrathecal application
eng
uncontrolled
NMOSD
eng
uncontrolled
aquaporin 4
eng
uncontrolled
autoantibody
eng
uncontrolled
IVIg
Medizin und Gesundheit
open_access
Neurologische Klinik und Poliklinik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/16600/Grunewald_IJMS_2016.pdf
17000
2017
eng
e28685
6
article
1
2018-10-25
--
--
Defective synaptic transmission causes disease signs in a mouse model of juvenile neuronal ceroid lipofuscinosis
Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease) caused by mutations in the CLN3 gene is the most prevalent inherited neurodegenerative disease in childhood resulting in widespread central nervous system dysfunction and premature death. The consequences of CLN3 mutation on the progression of the disease, on neuronal transmission, and on central nervous network dysfunction are poorly understood. We used Cln3 knockout (Cln3\(^{Δex1-6}\)) mice and found increased anxiety-related behavior and impaired aversive learning as well as markedly affected motor function including disordered coordination. Patch-clamp and loose-patch recordings revealed severely affected inhibitory and excitatory synaptic transmission in the amygdala, hippocampus, and cerebellar networks. Changes in presynaptic release properties may result from dysfunction of CLN3 protein. Furthermore, loss of calbindin, neuropeptide Y, parvalbumin, and GAD65-positive interneurons in central networks collectively support the hypothesis that degeneration of GABAergic interneurons may be the cause of supraspinal GABAergic disinhibition.
eLife
10.7554/eLife.28685
urn:nbn:de:bvb:20-opus-170004
eLife 2017, 6:e28685. DOI: 10.7554/eLife.28685
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Benedikt Grünewald
Maren D Lange
Christian Werner
Aet O'Leary
Andreas Weishaupt
Sandy Popp
David A Pearce
Heinz Wiendl
Andreas Reif
Hans C Pape
Klaus V Toyka
Claudia Sommer
Christian Geis
eng
uncontrolled
CLN3
eng
uncontrolled
mutation
eng
uncontrolled
mouse model
eng
uncontrolled
synaptic transmission
eng
uncontrolled
amygdala
eng
uncontrolled
hippocampus
Medizin und Gesundheit
open_access
Neurologische Klinik und Poliklinik
Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/17000/011_Grunewald_eLIFE.pdf