Kinboshi Masato, Shimizu Saki, Tokudome Kentaro, Mashimo Tomoji, Serikawa Tadao, Ito Hidefumi, Takahashi Ryosuke, Ikeda Akio, Ohno Yukihiro
Department of Pharmacology, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, 569-1094, Japan.
Department of Neurology, Wakayama Medical University, Wakayama, 641-8509, Japan.
Heliyon. 2023 Jul 5;9(7):e17984. doi: 10.1016/j.heliyon.2023.e17984. eCollection 2023 Jul.
() was identified as a causative gene of autosomal dominant lateral temporal lobe epilepsy. We previously reported that -mutant rats carrying a missense mutation (L385R) showed audiogenic seizure-susceptibility. To explore the pathophysiological mechanisms underlying Lgi1-related epilepsy, we evaluated changes in glutamate and GABA release in -mutant rats. Acoustic priming (AP) for audiogenic seizure-susceptibility was performed by applying intense sound stimulation (130 dB, 10 kHz, 5 min) on postnatal day 16. Extracellular glutamate and GABA levels in the hippocampus CA1 region were evaluated at 8 weeks of age, using microdialysis techniques. Under naïve conditions without AP, glutamate and GABA release evoked by high-K depolarization was more prominent in -mutant than in wild-type (WT) rats. The AP treatment on day 16 significantly increased basal glutamate levels and depolarization-induced glutamate release both in -mutant and WT rats, yielding greater depolarization-induced glutamate release in -mutant rats. On the other hand, the AP treatment enhanced depolarization-induced GABA release only in WT rats, and not in -mutant rats, illustrating reduced GABAergic neurotransmission in primed -mutant rats. The present results suggest that enhanced glutamatergic and reduced GABAergic neurotransmission are involved in the audiogenic seizure-susceptibility associated with -mutation.
（）被鉴定为常染色体显性外侧颞叶癫痫的致病基因。我们之前报道过，携带错义突变（L385R）的突变大鼠表现出对听源性癫痫发作的易感性。为了探究Lgi1相关癫痫的病理生理机制，我们评估了突变大鼠中谷氨酸和γ-氨基丁酸（GABA）释放的变化。在出生后第16天，通过施加强烈的声音刺激（130分贝，10千赫兹，5分钟）对听源性癫痫发作易感性进行声音启动（AP）。在8周龄时，使用微透析技术评估海马CA1区的细胞外谷氨酸和GABA水平。在没有AP的单纯条件下，高钾去极化诱发的谷氨酸和GABA释放在突变大鼠中比野生型（WT）大鼠中更显著。第16天的AP处理显著增加了突变大鼠和WT大鼠的基础谷氨酸水平以及去极化诱导的谷氨酸释放，在突变大鼠中产生了更大的去极化诱导的谷氨酸释放。另一方面，AP处理仅增强了WT大鼠中去极化诱导的GABA释放，而在突变大鼠中没有增强，这表明在启动的突变大鼠中GABA能神经传递减少。目前的结果表明，谷氨酸能增强和GABA能神经传递减少与突变相关的听源性癫痫发作易感性有关。
