Encephalitis patient derived monoclonal GABAAreceptor antibodies cause catatonia and epileptic seizures

Autoantibodies targeting the GABA A receptor (GABA A R) hallmark an autoimmune encephalitis presenting with frequent seizures and psychomotor abnormalities. Their pathogenic role is still not well-defined, given the common overlap with further autoantibodies and the lack of patient derived monoclonal antibodies (mAbs). We cloned and recombinantly produced five affinity-maturated GABA A R IgG1 mAbs from cerebrospinal fluid cells, which bound to various epitopes involving α1 and γ2 receptor subunits, with variable binding strength and partial competition. mAbs selectively reduced GABAergic currents in neuronal cultures without causing receptor internalization. Cerebroventricular infusion of GABA A R mAbs and Fab fragments into rodents induced a severe phenotype with catatonia, seizures and increased mortality, reminiscent of encephalitis patients’ symptoms. Our results prove direct functional effects of autoantibodies on GABA A Rs and provide an animal model for GABA A R encephalitis. They further provide the scientific rationale for clinical treatments using antibody depletion and pave the way for future antibody-selective immunotherapies.