Peripherally derived LGI1-reactive monoclonal antibodies cause epileptic seizuresin vivo

• DOI: 10.1101/2023.10.11.561725
• Publication Date: 2023-10-16T17:20:26Z
• Authors: Manoj Upadhya; Toni Kirmann; Max Wilson; Christian M Simon; Divya Dhangar; Christian Geis; Robyn Williams; Gavin Woodhall; Stefan Hallermann; Sarosh R Irani; Sukhvir K Wright
• Keywords: Male; Epilepsy; Seizures; Report; Intracellular Signaling Peptides and Proteins; Animals; Antibodies, Monoclonal; Humans; Proteins; Electroencephalography; Rats, Wistar; Rats; Autoantibodies

Abstract One striking clinical hallmark in patients with autoantibodies to leucine-rich glioma inactivated 1 (LGI1) is the very frequent focal seizure semiologies, including faciobrachial dystonic seizures (FBDS), addition amnesia. Polyclonal serum IgGs have successfully modelled cognitive changes vivo but not seizures. Hence, it remains unclear whether LGI1-autoantibodies are sufficient cause We tested this molecularly precise monoclonal antibodies directed against LGI1 (LGI1-mAbs), derived from patient circulating B cells. These were towards both major domains of LGI1, LRR (n=5) and EPTP infused intracerebroventricularly over 7 days into juvenile male Wistar rats using osmotic pumps. Continuous wireless EEG was recorded a depth electrode placed hippocampal CA3 plus behavioural tests for memory hyperexcitability performed. Following infusion completion (Day 9), post-mortem brain slices studied electrophysiology immunostaining. By comparison control-mAb injected (n=6), video-EEG analysis 9 revealed convulsive non-convulsive activity LGI1-mAbs, significant number ictal events (245±83 vs. 7.8±7.8 controls; p=0.002). Memory impaired novel object recognition test. Local field potential recordings postmortem showed spontaneous ictal-like spike region (p=0.03). The LGI1-mAbs bound most strongly induced reduction Kv1.1 cluster subfield (6 LGI1-mAbs; p=0.01) Peripherally-derived human rodent CSF provide strong evidence direct epileptogenesis molecular correlations. findings fulfill criteria LGI1-antibodies causation.