P4 Impact of IgLON5 autoantibodies on cerebellar circuits and neuronal pathology in human patients and mouse models

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Anti-IgLON5 disease is a novel form of autoimmune encephalitis, associated with antibodies against the cell-adhesion molecule IgLON5 and characterized by gait impairment, sleep abnormality and brainstem dysfunction. Autopsy studies revealed a peculiar tauopathy in the brainstem and cerebellum in some patients, while others show inflammatory infiltrates only, with variable deposits of IgG1 and 4. The synaptic and neuronal mechanisms underlying the anti-IgLON5-associated symptoms remain largely unknown. We thus propose to conduct comprehensive neuropathological investigations of autopsy tissue of nine IgLON5 patients (six with/three without tauopathy), to study inflammation, its impact on neurons and the intriguing link to neurodegeneration. We will next probe the role of different IgG subclasses on neuronal health in primary cultures. To gain insight into the pathomechanisms governing neuronal dysfunction, we will establish a mouse model of disease based on passive IgG1 or IgG4 intracerebroventricular transfer and characterize the binding pattern of anti-IgLON5, resulting behavioral deficits and assess neuronal structure and function in the cerebellar cortex of behaving mice by means of two-photon imaging.