Unité de Neurobiologie des canaux Ioniques et de la Synapse, Unité Mixte de Recherche 1072, Institut National de la Santé et de la Recherche Médicale, Aix-Marseille Université, Marseille, 13015, France.
Cajal Institute, Consejo Superior de Investigaciones Cientificas, Madrid, 28002, Spain.
J Neurosci. 2023 Dec 13;43(50):8596-8606. doi: 10.1523/JNEUROSCI.0701-23.2023.
Leucine-rich glioma inactivated 1 (LGI1) is a glycoprotein secreted by neurons, the deletion of which leads to autosomal dominant lateral temporal lobe epilepsy. We previously showed that LGI1 deficiency in a mouse model (i.e., knock-out for LGI1 or KO-Lgi1) decreased Kv1.1 channel density at the axon initial segment (AIS) and at presynaptic terminals, thus enhancing both intrinsic excitability and glutamate release. However, it is not known whether normal excitability can be restored in epileptic neurons. Here, we show that the selective expression of LGI1 in KO-Lgi1 neurons from mice of both sexes, using single-cell electroporation, reduces intrinsic excitability and restores both the Kv1.1-mediated D-type current and Kv1.1 channels at the AIS. In addition, we show that the homeostatic-like shortening of the AIS length observed in KO-Lgi1 neurons is prevented in neurons electroporated with the Lgi1 gene. Furthermore, we reveal a spatial gradient of intrinsic excitability that is centered on the electroporated neuron. We conclude that expression of LGI1 restores normal excitability through functional Kv1 channels at the AIS. The lack of leucine-rich glioma inactivated 1 (LGI1) protein induces severe epileptic seizures that leads to death. Enhanced intrinsic and synaptic excitation in KO-Lgi1 mice is because of the decrease in Kv1.1 channels in CA3 neurons. However, the conditions to restore normal excitability profile in epileptic neurons remain to be defined. We show here that the expression of LGI1 in KO-Lgi1 neurons in single neurons reduces intrinsic excitability, and restores both the Kv1.1-mediated D-type current and Kv1.1 channels at the axon initial segment (AIS). Furthermore, the homeostatic shortening of the AIS length observed in KO-Lgi1 neurons is prevented in neurons in which the Lgi1 gene has been rescued. We conclude that LGI1 constitutes a critical factor to restore normal excitability in epileptic neurons.
富含亮氨酸胶质瘤失活 1 型（LGI1）是一种由神经元分泌的糖蛋白，其缺失会导致常染色体显性颞叶外侧癫痫。我们之前的研究表明，在小鼠模型中（即敲除 LGI1 或 KO-Lgi1），LGI1 的缺乏会降低轴突起始段（AIS）和突触前末梢处的 Kv1.1 通道密度，从而增强内在兴奋性和谷氨酸释放。然而，尚不清楚在癫痫神经元中是否可以恢复正常的兴奋性。在这里，我们通过单细胞电穿孔显示，在雄性和雌性 KO-Lgi1 神经元中选择性表达 LGI1，可降低内在兴奋性，并恢复 AIS 处的 Kv1.1 介导的 D 型电流和 Kv1.1 通道。此外，我们还发现，在用电穿孔基因转染的神经元中，KO-Lgi1 神经元中观察到的 AIS 长度的类似稳态缩短被阻止。此外，我们揭示了内在兴奋性的空间梯度，该梯度以电穿孔神经元为中心。我们的结论是，LGI1 通过 AIS 处的功能性 Kv1 通道恢复正常的兴奋性。缺乏富含亮氨酸胶质瘤失活 1 型（LGI1）蛋白会导致严重的癫痫发作并导致死亡。KO-Lgi1 小鼠中的内在和突触兴奋性增强是由于 CA3 神经元中 Kv1.1 通道的减少。然而，在癫痫神经元中恢复正常兴奋性特征的条件仍有待确定。我们在这里表明，在单个神经元中的 KO-Lgi1 神经元中表达 LGI1 会降低内在兴奋性，并恢复 AIS 处的 Kv1.1 介导的 D 型电流和 Kv1.1 通道。此外，在已挽救 Lgi1 基因的神经元中，KO-Lgi1 神经元中观察到的 AIS 长度的稳态缩短被阻止。我们的结论是，LGI1 是恢复癫痫神经元正常兴奋性的关键因素。
