Project Details
Projekt
Molecular mechanisms and in-vivo functional effects of antibodies in GABAB receptor autoimmune encephalitis
Applicants
Professor Dr. Christian Geis; Dr. Hans-Christian Kornau; Professor Dr. Christoph Schmidt-Hieber
Subject Area
Molecular and Cellular Neurology and Neuropathology
Molecular Biology and Physiology of Neurons and Glial Cells
Molecular Biology and Physiology of Neurons and Glial Cells
Term
since 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 415914819
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.
DFG Programme
Research Units
