Glycine receptor autoantibodies and spinal disinhibition

甘氨酸受体（GlyR）自身抗体与儿童和成人僵硬人综合征和危及生命的进行性脑脊髓炎伴僵硬和肌阵挛相关。在之前的资助期内，我们发现自身抗体不仅针对突触后glyr，而且还可以结合突触前GlyRα亚基。此外，我们发现在某些情况下，自身抗体靶向突触后GlyRβ亚基。我们最近通过冷冻破裂和免疫金标记在超微结构分辨率下建立了GlyR场评估，将用于揭示不同的GlyR自身抗体与突触后GlyR结合后脊髓神经元中GlyR纳米级组织和可塑性的损伤。我们将揭示突触后GlyR的细胞内接头和支架蛋白如何促进自身抗体对GlyR纳米级组织和功能的影响。将研究自身抗体诱导的表面GlyRs动态变化的机制。根据我们的观察，GlyR自身抗体另外结合突触前GlyR，我们将确定自身抗体存在时突触前缺陷对疾病病理的贡献。通过这些策略，我们期望详细阐述GlyR自身抗体是否以及如何影响突触形态和可塑性，从而确定GlyR自身抗体病理的机制。

Glycine receptor (GlyR) autoantibodies are associated with stiff-person syndrome and the lifethreatening progressive encephalomyelitis with rigidity and myoclonus in children and adults. In the previous funding period, we uncovered that the autoantibodies are not only directed to postsynaptic GlyRs, but can also bind to presynaptic GlyRα subunits. Moreover, we found in some cases that autoantibodies target the postsynaptic GlyRβ subunit. Our recently established GlyR field evaluation at ultrastructural resolution by freeze-fracturing and immunogold labeling will be applied to reveal impairments of the nanoscale organization and plasticity of GlyRs in spinal cord neurons upon binding of distinct, characterized GlyR autoantibodies to postsynaptic GlyRs. We will unravel how intracellular adaptor and scaffolding proteins of the postsynaptic GlyR contribute to autoantibody effects on GlyR nanoscale organization and functionality. Autoantibody-induced mechanisms underlying dynamic changes of surface GlyRs will be investigated. Following our observation that GlyR autoantibodies additionally bind to presynaptic GlyRs we will determine the contribution of presynaptic defects upon autoantibody presence to disease pathology. With these strategies we expect to elaborate if and how GlyR autoantibodies influence synaptic morphology and plasticity and thus to identify mechanisms underlying GlyR autoantibody pathology.