UNIS, INSERM, Aix-Marseille Université, 13015 Marseille, France.
Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, Oxford University, Oxford OX3 9DU, UK.
Cells. 2022 Aug 31;11(17):2713. doi: 10.3390/cells11172713.
Leucine-rich Glioma-Inactivated protein 1 (LGI1) is expressed in the central nervous system and its genetic loss of function is associated with epileptic disorders. 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.
富含亮氨酸胶质瘤失活 1 蛋白 (LGI1) 在中枢神经系统中表达，其基因功能丧失与癫痫疾病有关。此外，LGI1 定向自身抗体的患者常以局灶性癫痫发作为其疾病的主要特征。LGI1 由亮氨酸丰富重复 (LRR) 和 Epitempin (EPTP) 结构域组成。据报道，这些结构域与 LGI1 在兴奋性突触形成的突触后复合物中的不同成员相互作用，包括突触前 Kv1 钾通道。患者来源的重组单克隆抗体 (mAb) 是研究特定结构域的 LGI1 自身抗体是否在神经元中诱导癫痫样活动及其下游机制的理想试剂。我们测量了用 LRR 或 EPTP 反应性患者来源的 mAb 或对照患者 IgG 处理的大鼠海马器官型培养物中 CA3 锥体神经元的固有兴奋性。我们发现，与用 EPTP mAb 处理的神经元相比，用 LRR mAb 处理的神经元的固有兴奋性增加，并且对选择性 Kv1.1 通道阻滞剂的敏感性降低。我们的研究结果表明，LRR mAb 能够调节神经元兴奋性，这可能是患者中观察到癫痫样活动的原因。
