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