Medical Scientist-Programm 2025

Thema: "Pathophysiological effects of human autoantibodies against the structural protein Caspr2 in the central nervous system"

Zusammenfassung:
Autoimmune encephalitis (AE) with anti-Caspr2 autoantibodies (aAb) affects the central and peripheral nervous system (CNS / PNS), causing diverse symptoms including anterograde amnesia, behavioral disorders, epileptic seizures (CNS involvement), neuropathic pain, and movement disorders (PNS involvement). Previous studies suggest an aAb-mediated disruption of Caspr2 interactions with TAG-1 and Kv1 potassium channels. However, the precise localization and function of Caspr2 in neurons remained unclear and the pathomechanisms underlying characteristic AE symptoms are largely unknown. This study aims to elucidate the impact of aAb on Caspr2 expression, synaptic localization, and its interaction with binding partners using high-resolution imaging. Electrophysiological studies in established mouse models will investigate disturbances in synaptic transmission potentially caused by altered Kv1 channel formation. Furthermore, the study will examine how defects in molecular interactions and cellular activity contribute to network dysfunction, leading to memory disorders and epilepsy, through ex-vivo and in-vivo recordings of network oscillations and ictal activity, alongside behavioral tests. Utilizing human monoclonal antibodies with distinct epitope reactivity will allow for the determination of Caspr2 subunit-specific effects. The findings will enhance our understanding of an enigmatic autoimmune disease of the nervous system and might contribute to the development of targeted treatment strategies, e.g. by modulation of Kv1 channel activity.