Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Mol Brain. 2024 Nov 29;17(1):91. doi: 10.1186/s13041-024-01164-9.
Temporal lobe epilepsy (TLE) is the most common form of medically-intractable epilepsy. Subicular hyperexcitability is frequently observed with TLE, presumably caused by impaired inhibition of local excitatory neurons. Here, we evaluated the effectiveness of silencing subicular pyramidal neurons to treat a rodent model of TLE. First, we generated a chronic TLE mouse model via initial intrahippocampal kainic acid (IHKA) injection. In the chronic state after first IHKA injection, behavioral seizures and histological abnormalities were reliably observed. We then injected an adeno-associated viral (AAV) vector carrying an inhibitory chemogenetic element, hM4D, directly into the subiculum. Eight weeks after the first IHKA injection, acute seizures were induced by giving a second dose of kainic acid (KA), which mimicked generalized tonic-clonic seizures. Herein, precise control over generalized tonic-clonic seizure onset was achieved via this two-step process. We found that chemogenetic suppression of subicular pyramidal neurons had a robust anti-epileptogenesis effect in this acute-chronic model of TLE. These data confirm a crucial role of the subiculum in the propagation of hippocampal seizures and highlight the potential for using subicular chemogenetic manipulation to treat generalized tonic-clonic seizures.
颞叶癫痫（TLE）是最常见的药物难治性癫痫形式。TLE 常伴有海马回过度兴奋，推测是由局部兴奋性神经元抑制受损引起的。在这里，我们评估了沉默海马回锥体神经元治疗 TLE 啮齿动物模型的效果。首先，我们通过海马内海人酸（IHKA）初次注射来生成慢性 TLE 小鼠模型。在初次 IHKA 注射后的慢性状态下，可靠地观察到行为性癫痫发作和组织学异常。然后，我们将携带抑制性化学遗传学元件 hM4D 的腺相关病毒（AAV）载体直接注射到海马回。在初次 IHKA 注射 8 周后，通过给予第二次海人酸（KA）剂量来诱导急性发作，这模拟了全面强直阵挛性发作。在此，通过两步过程可以精确控制全面强直阵挛性发作的起始。我们发现，化学遗传学抑制海马回锥体神经元在 TLE 的这种急性慢性模型中具有强大的抗癫痫发生作用。这些数据证实了海马回在海马回发作传播中的关键作用，并强调了使用海马回化学遗传学操作治疗全面强直阵挛性发作的潜力。
