Molecular mechanisms and in-vivo functional effects of antibodies in GABAB receptor autoimmune encephalitis

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Patients with GABAB receptor encephalitis show a characteristic syndrome of limbic encephalitis including anterograde memory dysfunction and severe seizures. In the past funding period, we established a passive-transfer mouse model using patient-derived polyclonal GABAB receptor antibodies resulting in memory dysfunction comparable to GABAB1a knockout mice. Moreover, we uncovered a predominant effect of GABAB receptor antibodies on presynaptic auto- and heteroreceptors whereas postsynaptic GABAB receptor induced GIRK channel activation and hyperpolarization were unaffected. In the present proposal we aim towards production of patient-derived monoclonal GABAB receptor antibodies to explore the molecular effects of antibodies on the GABAB receptor and downstream pathomechanisms. We will proceed to combined in-vivo recording, imaging, and behavioral analysis to investigate the antibodies’ effect on epileptogenesis and hippocampus-dependent learning and memory dysfunction. To this end, we aim towards understanding antibody-induced defects of cellular excitability and hippocampal circuits. By site-specific antibody-neutralization in-vivo using GABAB1/2-ECD-Fc fusion proteins we plan to determine vulnerable regions of GABAB receptor pathology in the hippocampus that are critical for epilepsy and cognitive dysfunction. Finally, we will validate if patient-derived GABAB receptor antibodies induce similar synaptic pathology also in human iPSC derived neurons and human brain tissue.