Glycine receptor autoantibodies and spinal disinhibition

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Glycine receptor (GlyR) autoantibodies are associated with stiff-person syndrome and the life-threatening progressive encephalomyelitis with rigidity and myoclonus in children and adults. Recently, we found that patient IgG binds to various GlyRbeta subunits and reduces GlyR function in transfected cells. Here, we will investigate short- and long-term effects of GlyR autoantibodies on synaptic function, GlyR internalization, and GlyR ion channel function using electrophysiological measurements and super-resolution imaging techniques. We will examine novel GlyR-autoantibody targets such a presynaptic GlyRalpha or GlyRbeta. GlyR and GABAA receptor function will be studied at central synapses upon application of patient IgG using established brain stem slice preparations. Phenotypic behavioral changes will be determined after passive-transfer in mice and spinal glycinergic inhibition will be evaluated in vivo. We will identify the GlyR-autoantibody producing cells from patient blood and CSF with the aim to improve therapeutic options. With these data we expect to clarify if and how functional synaptic disruption underlies the GlyR autoantibody pathology. Based on these findings we aim to identify novel strategies for potential therapeutic intervention in GlyR autoantibody-associated diseases.