Glycine receptor autoantibodies and spinal disinhibition

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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.