The functional impact of LGI1 autoantibodies on human CA3 pyramidal neurons.

Autoantibodies against leucine-rich glioma inactivated 1 protein (LGI1) lead to limbic encephalitis, a rare neurological autoimmune disorder characterized by faciobrachial dystonic seizures and memory deficits. While animal models provide precious insights into the mechanisms of LGI1 autoantibody action, species-specific confirmation is lacking. In this study, we investigated the effects of patient-derived LGI1 monoclonal antibodies (LGI1 mAb) on CA3 pyramidal neurons using cultured ex vivo human hippocampal slices, providing a unique platform to study disease mechanisms in a homologous, clinically relevant context. Under incubation conditions, human CA3 neurons preserved their morphology, were intrinsically excitable and received spontaneous excitatory currents with large amplitudes and frequencies suggestive of "giant" AMPA receptor-mediated currents. In slices exposed to LGI1 mAb, human CA3 pyramidal neurons displayed increased action potential (AP) firing frequency, mirroring the effects observed with the Kv1.1 channel blocker dendrotoxin-K (DTX-K). This increase likely resulted from a decreased Kv1.1 channel activity at the axonal initial segment, as indicated by alterations in AP properties, including spike latency at rheobase and depolarizing ramp slope. Differences between LGI1 mAb and DTX-K effects on some AP properties suggested distinct mechanisms of action and emphasized the need for further exploration of downstream pathways. Our findings underscore the importance of species-specific confirmatory studies of disease mechanisms and give insight into possibilities and limitations of human hippocampal slice cultures as a translational model for the investigation of disease mechanisms beyond epilepsy, including the effects of pharmacological compounds and autoantibodies.