Pathogenic Role of Autoantibodies Against GABAergic Target Molecules

Anna Braun1, Dr. Julika Pitsch1, Prof. Dr. Albert Becker1

1 Universitätsklinikum Bonn, Institut für Neuropathologie

Limbic encephalitis (LE) is increasingly recognized as a trigger of adult-onset temporal lobe epilepsy, resulting in seizures, memory impairment and hippocampal sclerosis (HS). In many patients LE is associated with specific auto-antibodies (ABs) but the role of most ABs remains vague and it is still unresolved whether they have a pathogenic significance or act as potential biomarkers.

ABs directed against molecules important for GABAergic function in several brain structures such as γ-aminobutyric acid type A receptors (GABAAR) and glutamic acid decarboxylase 65 (GAD65) are found in LE but the pathogenic mechanisms mediating epileptogenesis are only insufficiently understood.

Patient-derived anti-GABAAR ABs can decrease synaptic and surface GABAA receptors and selectively reduce miniature IPSC amplitude and frequency of cultured neurons. However, HS is frequently found in anti-GAD65 AB positive patients although exposure of normal hippocampal tissue to anti-GAD65 ABs did not result in functional impairment.

In order to examine effects of patient anti-GAD65 and anti-GABAAR ABs, we induced neuronal endocytosis and scrutinized for internalization of ABs determining probable changes of GABA release in vitro. Subsequently, we successfully demonstrated the internalization of GABAA receptors after incubation with monoclonal anti-GABAAR ABs derived from an LE patient. We exposed primary neurons to anti-GAD65 as well as anti-GABAAR ABs individually and tested for functional consequences on in vitro neuronal network activity (ivNNA) using multi-electrode-arrays (MEAs).

By these experiments, we expect fundamentally improved perceptions of anti-GAD65- and anti-GABAAR-ABs impact on the development and progression of LE with important neuroimmunological and prospective therapeutic approaches.

Acknowledgement: Our work is generously supported by EKFS graduate program ‘NeuroImmunology’