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Additionally, patients with LGI1-directed autoantibodies have frequent focal seizures as a key feature of their disease. LGI1 is composed of a Leucine-Rich Repeat (LRR) and an Epitempin (EPTP) domain. These domains are reported to interact with different members of the transsynaptic complex formed by LGI1 at excitatory synapses, including presynaptic Kv1 potassium channels. Patient-derived recombinant monoclonal antibodies (mAbs) are ideal reagents to study whether domain-specific LGI1-autoantibodies induce epileptiform activities in neurons and their downstream mechanisms. We measured the intrinsic excitability of CA3 pyramidal neurons in organotypic cultures from rat hippocampus treated with either an LRR- or an EPTP-reactive patient-derived mAb, or with IgG from control patients. We found an increase in intrinsic excitability correlated with a reduction of the sensitivity to a selective Kv1.1-channel blocker in neurons treated with the LRR mAb, but not in neurons treated with the EPTP mAb. Our findings suggest LRR mAbs are able to modulate neuronal excitability that could account for epileptiform activity observed in patients.<\/jats:p>","DOI":"10.3390\/cells11172713","type":"journal-article","created":{"date-parts":[[2022,8,31]],"date-time":"2022-08-31T23:53:21Z","timestamp":1661990001000},"page":"2713","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["An Epitope-Specific LGI1-Autoantibody Enhances Neuronal Excitability by Modulating Kv1.1 Channel"],"prefix":"10.3390","volume":"11","author":[{"given":"Johanna","family":"Extr\u00e9met","sequence":"first","affiliation":[{"name":"UNIS, INSERM, Aix-Marseille Universit\u00e9, 13015 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7473-8345","authenticated-orcid":false,"given":"Oussama","family":"El Far","sequence":"additional","affiliation":[{"name":"UNIS, INSERM, Aix-Marseille Universit\u00e9, 13015 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Ankri","sequence":"additional","affiliation":[{"name":"UNIS, INSERM, Aix-Marseille Universit\u00e9, 13015 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7667-9748","authenticated-orcid":false,"given":"Sarosh R.","family":"Irani","sequence":"additional","affiliation":[{"name":"Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, Oxford University, Oxford OX3 9DU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8581-5695","authenticated-orcid":false,"given":"Dominique","family":"Debanne","sequence":"additional","affiliation":[{"name":"UNIS, INSERM, Aix-Marseille Universit\u00e9, 13015 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1401-9389","authenticated-orcid":false,"given":"Micha\u00ebl","family":"Russier","sequence":"additional","affiliation":[{"name":"UNIS, INSERM, Aix-Marseille Universit\u00e9, 13015 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1002\/ana.22307","article-title":"Faciobrachial Dystonic Seizures Precede Lgi1 Antibody Limbic Encephalitis","volume":"69","author":"Irani","year":"2011","journal-title":"Ann Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.seizure.2017.05.017","article-title":"LGI1-Antibody Encephalitis Is Characterised by Frequent, Multifocal Clinical and Subclinical Seizures","volume":"50","author":"Aurangzeb","year":"2017","journal-title":"Seizure"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1093\/brain\/awx323","article-title":"The Importance of Early Immunotherapy in Patients with Faciobrachial Dystonic Seizures","volume":"141","author":"Thompson","year":"2018","journal-title":"Brain"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1111\/j.1528-1167.2010.02756.x","article-title":"Human Limbic Encephalitis Serum Enhances Hippocampal Mossy Fiber-CA3 Pyramidal Cell Synaptic Transmission: Limbic Encephalitis in the Hippocampus","volume":"52","author":"Lalic","year":"2011","journal-title":"Epilepsia"},{"key":"ref_5","first-page":"3144","article-title":"LGI1 Antibodies Alter Kv1.1 and AMPA Receptors Changing Synaptic Excitability, Plasticity and Memory","volume":"141","author":"Sell","year":"2018","journal-title":"Brain"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1007\/s00018-019-03269-0","article-title":"Insights into the Mechanisms of Epilepsy from Structural Biology of LGI1\u2013ADAM22","volume":"77","author":"Yamagata","year":"2020","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1002\/ana.25666","article-title":"Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability","volume":"87","author":"Kornau","year":"2020","journal-title":"Ann. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1093\/brain\/awaa104","article-title":"Distinctive Binding Properties of Human Monoclonal LGI1 Autoantibodies Determine Pathogenic Mechanisms","volume":"143","author":"Ramberger","year":"2020","journal-title":"Brain"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"18161","DOI":"10.1523\/JNEUROSCI.3506-13.2013","article-title":"Autoantibodies to Epilepsy-Related LGI1 in Limbic Encephalitis Neutralize LGI1-ADAM22 Interaction and Reduce Synaptic AMPA Receptors","volume":"33","author":"Ohkawa","year":"2013","journal-title":"J. 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