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LAMBERT EATON MYASTHENIC SYNDROME ANTIBODIES DECREASE SYNAPTIC VESICLE EXOCYTOSIS IN NEURONAL CULTURES
  1. Jennifer Spillane,
  2. YE Ermolyuk,
  3. KE Volynski,
  4. DM Kullmann
  1. Institute of Neurology, UCL

    Abstract

    Lambert Eaton Myasthenic Syndrome (LEMS) is an autoimmune disorder characterised by proximal muscle weakness and autonomic symptoms. Approximately 60% of cases are paraneoplastic. Antibodies to presynaptic voltage gated calcium channels of the P/Q–type are detected in 92% of LEMS patients. Presynaptic voltage gated calcium channels (VGCCs) both P/Q–and N–type, are the major trigger of action potential evoked release of neurotransmitters at peripheral and central synapses. Passive transfer of LEMS IgG to mice has been shown to reduce end plate potentials at the neuromuscular junction, suggesting that LEMS is caused by inhibition of neurotransmitter release. However, a direct effect of LEMS IgG on synaptic vesicular exocytosis has not been demonstrated.

    We tested the effects of LEMS IgG on synaptic vesicle exocytosis in dissociated hippocampal neuronal cultures. We compared the effects of chronic application (16 hours) of LEMS IgG from three separate LEMS patients and three control subjects on action potential–evoked vesicular release using fluorescence imaging of the styryl FM dye SynaptoRedC1 (SRC1). Recycling vesicles were labelled with SRC1 using high frequency field stimulation. Subsequent stimulation at 0.5 Hz triggered release of the trapped SRC1 dye from exocytosing vesicles, and the rate of fluorescence loss in individual synaptic boutons was used as a measure of the rate of vesicular exocytosis. The rate of action potential–evoked synaptic vesicle exocytosis was significantly decreased in LEMS treated neurones in comparison to neurones treated with control IgG. Spontaneous vesicular release was unaffected by LEMS IgG. Our results provide evidence that LEMS IgG can directly inhibit action potential–evoked synaptic vesicle release.

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