Stiff person syndrome-associated autoantibodies to amphiphysin mediate reduced GABAergic inhibition

被引:137
作者
Geis, Christian [1 ]
Weishaupt, Andreas [1 ]
Hallermann, Stefan [2 ,3 ]
Gruenewald, Benedikt [1 ]
Wessig, Carsten [1 ]
Wultsch, Thomas [4 ]
Reif, Andreas [4 ]
Byts, Nadiya [5 ]
Beck, Marcus [1 ]
Jablonka, Sibylle [2 ]
Boettger, Michael K. [1 ,6 ]
Ueceyler, Nurcan [1 ]
Fouquet, Wernher [2 ,7 ]
Gerlach, Manfred [8 ]
Meinck, Hans-Michael [9 ]
Siren, Anna-Leena [5 ]
Sigrist, Stephan J. [2 ,7 ]
Toyka, Klaus V. [1 ]
Heckmann, Manfred [1 ,2 ,3 ,7 ,10 ]
Sommer, Claudia [1 ]
机构
[1] Univ Wurzburg, Dept Neurol, D-97080 Wurzburg, Germany
[2] Univ Wurzburg, Inst Clin Neurobiol, D-97080 Wurzburg, Germany
[3] Univ Leipzig, Carl Ludwig Inst Physiol, D-04103 Leipzig, Germany
[4] Univ Wurzburg, Dept Psychiat, D-97080 Wurzburg, Germany
[5] Univ Wurzburg, Dept Neurosurg, D-97080 Wurzburg, Germany
[6] Univ Hosp Jena, Inst Physiol 1, D-07743 Jena, Germany
[7] Deutsch Forsch Gemeinschaft Res Ctr Expt Biomed, Rudolf Virchow Ctr, D-97080 Wurzburg, Germany
[8] Univ Wurzburg, Dept Child & Adolescent Psychiat, D-97080 Wurzburg, Germany
[9] Heidelberg Univ, Dept Neurol, D-69120 Heidelberg, Germany
[10] Univ Wurzburg, Inst Physiol, D-97080 Wurzburg, Germany
关键词
stiff person syndrome; GABA; amphiphysin; patch clamp; STED microscopy; SYNAPTIC VESICLE ENDOCYTOSIS; EATON MYASTHENIC SYNDROME; GUILLAIN-BARRE-SYNDROME; MOTOR-NERVE TERMINALS; RAT SPINAL-CORD; PRESYNAPTIC INHIBITION; PASSIVE TRANSFER; NEUROMYELITIS-OPTICA; IMMUNOGLOBULIN-G; IGG ANTIBODIES;
D O I
10.1093/brain/awq253
中图分类号
R74 [神经病学与精神病学];
学科分类号
100204 [神经病学];
摘要
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 gamma-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.
引用
收藏
页码:3166 / 3180
页数:15
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