Baudin Paul, Whitmarsh Stephen, Cousyn Louis, Roussel Delphine, Lecas Sarah, Lehongre Katia, Charpier Stéphane, Mahon Séverine, Navarro Vincent
Sorbonne Université, Paris Brain Institute - Institut du Cerveau, ICM, INSERM, CNRS, APHP, Pitié-Salpêtrière Hospital, Paris, France.
Sorbonne Université, Paris Brain Institute - Institut du Cerveau, ICM, INSERM, CNRS, APHP, Pitié-Salpêtrière Hospital, Paris, France; AP-HP, Epilepsy Unit, Pitié-Salpêtrière Hospital, DMU Neurosciences, Paris, France.
Prog Neurobiol. 2022 Jun;213:102262. doi: 10.1016/j.pneurobio.2022.102262. Epub 2022 Mar 10.
Autoimmune encephalitis associated with antibodies directed against the leucine-rich glioma inactivated 1 (LGI1) protein is responsible for specific tonic-dystonic motor seizures. Although dysfunctions in neuronal excitability have been associated with anti-LGI1 autoantibodies, their relation to seizures remain inconclusive. We developed a new in vivo experimental rat model to determine whether inhibition of Kv1.1 channels by dentrotoxin-K (DTX) in the primary motor cortex (M1) could recapitulate the human seizures and to elucidate their subtending cortical mechanisms. Comparing electro-clinical features of DTX-induced seizures in rats with those recorded from a cohort of anti-LGI1 encephalitis patients revealed striking similarities in their electroencephalographic (EEG) signature, frequency of recurrence and semiology. By combining multi-site extracellular and intracellular recordings of M1 pyramidal neurons in DTX rats, we demonstrated that the blockade of Kv1.1 channels induced a sequence of changes in neuronal excitability and synaptic activity, leading to massive suprathreshold membrane depolarizations underlying the paroxysmal EEG activity. Our results suggest the central role of Kv1.1 channels disruption in the emergence of anti-LGI1-associated seizures and suggest that this new rodent model could serve future investigations on ictogenesis in autoimmune encephalitis.
与抗富含亮氨酸胶质瘤失活1（LGI1）蛋白抗体相关的自身免疫性脑炎可导致特定的强直性 - 肌张力障碍性运动性癫痫发作。尽管神经元兴奋性障碍与抗LGI1自身抗体有关，但其与癫痫发作的关系仍不明确。我们开发了一种新的体内实验大鼠模型，以确定原发性运动皮层（M1）中的蝰蛇毒素 - K（DTX）对Kv1.1通道的抑制是否能重现人类癫痫发作，并阐明其潜在的皮层机制。将DTX诱导的大鼠癫痫发作的电 - 临床特征与一组抗LGI1脑炎患者记录的特征进行比较，发现它们在脑电图（EEG）特征、复发频率和症状学方面有惊人的相似之处。通过结合DTX大鼠M1锥体神经元的多部位细胞外和细胞内记录，我们证明Kv1.1通道的阻断诱导了神经元兴奋性和突触活动的一系列变化，导致阵发性EEG活动背后的大量阈上膜去极化。我们的结果表明Kv1.1通道破坏在抗LGI1相关癫痫发作的发生中起核心作用，并表明这种新的啮齿动物模型可用于未来自身免疫性脑炎癫痫发生机制的研究。
