Patient-derived recombinant autoantibodies reveal the subcellular neuroglial distribution and heterogeneous interactome of leucine-rich glioma-inactivated 1

Autoantibodies against leucine-rich glioma-inactivated 1 (LGI1) occur in patients with encephalitis who present with frequent focal seizures and a pattern of amnesia consistent with focal hippocampal damage. To investigate whether the cellular and subcellular distribution of LGI1 may explain the localisation of these features, and gain broader insights into LGI1’s neurobiology, we analysed the detailed distribution of LGI1, and the diversity of its protein interactome, in mouse brains using recombinant monoclonal LGI1-antibodies derived from encephalitis patients. Combined immunofluorescence and mass spectrometry analyses showed that LGI1 is enriched in excitatory and inhibitory synaptic contact sites, most densely within CA3 regions of the hippocampus. LGI1 is secreted in both neuronal somatodendritic and axonal compartments, and occurs in oligodendrocytic, neuro-oligodendrocytic and astro-microglial protein complexes. Proteomic data support the hypothesis that destabilization of Kv1 / MAGUK complexes by autoantibodies could promote excitability, but did not reveal LGI1 complexes with postsynaptic glutamate receptors. Our results extend our understanding of regional, cellular and subcellular LGI1 expression profiles and reveal novel LGI1-associated complexes, thus providing insights into the complex biology of LGI1 and its relationship to seizures and memory loss.