LGI1 antibody-induced pathophysiology in synapses

Autoimmune encephalitis is caused by antibodies against own proteins, called autoantibodies. The aim of this project is to examine the second most common subtype of autoimmune encephalitis, caused by autoantibodies against a leucine-rich glioma inactivated 1 (LGI1) protein. Patients rapidly develop mood changes, anxiety, and dramatic loss of the ability to form new memories. The function of LGI1 protein is poorly understood but it interacts with membrane proteins at synapses, connections between neurons, and seems to affect key molecules in synaptic communication in the brain. We will resolve the localization and function of these proteins at the synapse and how the LGI1 autoantibodies interfere with their assembly and functions. These results will elucidate the mechanisms of the disease possibly leading to improved treatment of LGI1 antibody-induced encephalitis.

Autoimmune encephalitis is a growing group of diseases caused by autoantibodies against various neuronal antigens, collectively leading to severe mental and behavioral disorders. Limbic encephalitis, primarily hippocampus and amygdala is characterized by epileptic episodes and mood changes and amnesia. One of the most frequent type of autoimmune encephalitis is caused by autoantibodies against the neuronal protein leucine-rich glioma inactivated 1 (LGI1) resulting in characteristic dystonic and generalized seizures together with mnestic deficits. Seizures rapidly respond to immunotherapy, while patients often develop progressive cognitive impairment if treatment is delayed. To study the function of LGI1 at synapses and the consequence of disturbed LGI1 signaling, synaptic LGI1 function was studied using patient-derived polyclonal LGI1 autoantibodies. Incubation with autoantibodies reduced postsynaptic glutamate receptors increased presynaptic release probability and overall synaptic strength with strengthening paralleled by potassium channel loss. However, the mechanism by which LGI1 autoantibodies strengthen presynaptic neurotransmitter release and the responsible molecular domains remain elusive. We combined electrophysiological somatic and subcellular presynaptic recordings from hippocampal neurons with super-resolution microscopy and electron microscopy to identify mechanisms involved in the LGI1 autoantibody-mediated increase in presynaptic release. We find that polyclonal LGI1 autoantibodies increase presynaptic release probability independent of voltage-gated calcium channels. In contrast, polyclonal LGI1 autoantibodies reduce presynaptic voltage-gated potassium channels and lead to increased action potential broadening, which causes increased excitability of neuronal terminals. Thus, our study provides a mechanistic framework explaining the neuronal hyperactivity of patients with LGI1 antibody encephalitis, which may underlie the cause of seizures in anti-LGI1 encephalitis in order to develop effective, causative and symptomatic treatment.