| |  Online-Ressource |
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| Verfasst von: | Geis, Christian [VerfasserIn]  |
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| | Weishaupt, Andreas [VerfasserIn] |
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| | Hallermann, Stefan [VerfasserIn] |
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| | Grünewald, Benedikt [VerfasserIn] |
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| | Wessig, Carsten [VerfasserIn] |
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| | Wultsch, Thomas [VerfasserIn] |
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| | Reif, Andreas [VerfasserIn] |
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| | Byts, Nadiya [VerfasserIn] |
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| | Beck, Marcus [VerfasserIn] |
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| | Jablonka, Sibylle [VerfasserIn] |
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| | Boettger, Michael K. [VerfasserIn] |
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| | Üçeyler, Nurcan [VerfasserIn] |
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| | Fouquet, Wernher [VerfasserIn] |
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| | Gerlach, Manfred [VerfasserIn] |
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| | Meinck, Hans-Michael [VerfasserIn] |
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| | Sirén, Anna-Leena [VerfasserIn] |
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| | Sigrist, Stephan J. [VerfasserIn] |
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| | Toyka, Klaus Viktor [VerfasserIn] |
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| | Heckmann, Manfred [VerfasserIn] |
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| | Sommer, Claudia [VerfasserIn] |
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| Titel: | Stiff person syndrome-associated autoantibodies to amphiphysin mediate reduced GABAergic inhibition |
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| Verf.angabe: | Christian Geis, Andreas Weishaupt, Stefan Hallermann, Benedikt Grünewald, Carsten Wessig, Thomas Wultsch, Andreas Reif, Nadiya Byts, Marcus Beck, Sibylle Jablonka, Michael K. Boettger, Nurcan Üçeyler, Wernher Fouquet, Manfred Gerlach, Hans-Michael Meinck, Anna-Leena Sirén, Stephan J. Sigrist, Klaus V. Toyka, Manfred Heckmann and Claudia Sommer |
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| E-Jahr: | 2010 |
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| Jahr: | 30 September 2010 |
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| Umfang: | 15 S. |
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| Fussnoten: | Gesehen am 24.02.2023 |
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| Titel Quelle: | Enthalten in: Brain |
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| Ort Quelle: | Oxford : Oxford Univ. Press, 1878 |
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| Jahr Quelle: | 2010 |
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| Band/Heft Quelle: | 133(2010), 11, Seite 3166-3180 |
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| ISSN Quelle: | 1460-2156 |
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| Abstract: | Synaptic inhibition is a central factor in the fine tuning of neuronal activity in the central nervous system. Symptoms consistent with reduced inhibition such as stiffness, spasms and anxiety occur in paraneoplastic stiff person syndrome with autoantibodies against the intracellular synaptic protein amphiphysin. Here we show that intrathecal application of purified anti-amphiphysin immunoglobulin G antibodies induces stiff person syndrome-like symptoms in rats, including stiffness and muscle spasms. Using in vivo recordings of Hoffmann reflexes and dorsal root potentials, we identified reduced presynaptic GABAergic inhibition as an underlying mechanism. Anti-amphiphysin immunoglobulin G was internalized into neurons by an epitope-specific mechanism and colocalized in vivo with presynaptic vesicular proteins, as shown by stimulation emission depletion microscopy. Neurons from amphiphysin deficient mice that did not internalize the immunoglobulin provided additional evidence of the specificity in antibody uptake. GABAergic synapses appeared more vulnerable than glutamatergic synapses to defective endocytosis induced by anti-amphiphysin immunoglobulin G, as shown by increased clustering of the endocytic protein AP180 and by defective loading of FM 1-43, a styryl dye used to label cell membranes. Incubation of cultured neurons with anti-amphiphysin immunoglobulin G reduced basal and stimulated release of γ-aminobutyric acid substantially more than that of glutamate. By whole-cell patch-clamp analysis of GABAergic inhibitory transmission in hippocampus granule cells we showed a faster, activity-dependent decrease of the amplitude of evoked inhibitory postsynaptic currents in brain slices treated with antibodies against amphiphysin. We suggest that these findings may explain the pathophysiology of the core signs of stiff person syndrome at the molecular level and show that autoantibodies can alter the function of inhibitory synapses in vivo upon binding to an intraneuronal key protein by disturbing vesicular endocytosis. |
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| DOI: | doi:10.1093/brain/awq253 |
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| URL: | Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.
DOI: https://doi.org/10.1093/brain/awq253 |
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| Datenträger: | Online-Ressource |
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| Sprache: | eng |
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| Sach-SW: | Humans |
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| | Aged |
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| | Female |
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| | Middle Aged |
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| | Animals |
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| | Mice |
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| | Rats |
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| | Cells, Cultured |
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| | Mice, Knockout |
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| | Autoantibodies |
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| | Endocytosis |
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| | gamma-Aminobutyric Acid |
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| | Immunization, Passive |
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| | Immunoglobulin G |
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| | Inhibitory Postsynaptic Potentials |
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| | Injections, Spinal |
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| | Nerve Tissue Proteins |
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| | Neural Inhibition |
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| | Rats, Inbred Lew |
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| | Stiff-Person Syndrome |
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| K10plus-PPN: | 1837330514 |
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| Verknüpfungen: | → Zeitschrift |
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Stiff person syndrome-associated autoantibodies to amphiphysin mediate reduced GABAergic inhibition / Geis, Christian [VerfasserIn]; 30 September 2010 (Online-Ressource)
