LGI1 antibody-induced pathophysiology in synapses

Autoimmune encephalitis is an inflammation in the brain and is caused by antibodies against self-proteins generated by human patients (autoantibodies). If it occurs in the limbic systema set of brain regions involved in emotional and motivational processes and memory formationit is referred to as limbic encephalitis. Limbic encephalitis is the second most common subtype of autoimmune encephalitis in humans. It has devastating effects on patients, who are suffering from epilepsy, memory loss, and cognitive impairment. The autoantibodies that cause this disease target the protein leucine-rich glioma inactivated 1 (LGI1). The function of LGI1, however, remains poorly understood. There is evidence that LGI1 is secreted by neuronal cells (neurons) and forms a protein complex between two neurons making synaptic contacts, called trans-synaptic complex. LGI1 also controls the function of the axon initial segment (AIS)a specific membrane compartment of the axon near the neuronal cell, which generates action potential firing of neurons. In recent work, we found that pathogenic LGI1 antibodies might make neurons more easily excitable at the AIS. They also induce a more frequent release of vesicles at synapses, which could be due to the reduction of specific types of ion channels permeable for potassium in the axon terminal. This alteration causes a broadening of presynaptic action potential and an increase of calcium influx into the axon terminals, resulting in more frequent vesicle release. To uncover the underlying mechanisms of these LGI1 antibody-mediated changes, we will study the protein composition and function of the LGI1 complex at the AIS. Furthermore, we will investigate the LGI1 proteins role in the establishment of trans- synaptic protein complexes. For these purposes, we will visualize the synaptic vesicles and ion channels involved in the regulation of vesicle release in the axon terminals, by electron microscopy. Additionally, with the help of biochemical methods and proteomics, we will examine the composition of the LGI1 protein complex. These results will improve our understanding of the multiple roles of the LGI1 protein and will elucidate autoantibody-induced mechanisms, which could lead to better treatment of limbic encephalitis.