Department of Biology and Brain Health Consortium, University of Texas at San Antonio, San Antonio, Texas 78249, and.
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
J Neurosci. 2019 Aug 28;39(35):7019-7028. doi: 10.1523/JNEUROSCI.0920-19.2019. Epub 2019 Jul 15.
Mesial temporal lobe epilepsy (mTLE), the most common form of medically refractory epilepsy in adults, is usually associated with hippocampal pathophysiology. Using rodent models of mTLE, many studies including work from our laboratory have shown that new neurons born around the onset of severe acute seizures known as status epilepticus (SE) are crucial for the process of epileptogenesis and targeting seizure-induced neurogenesis either genetically or pharmacologically can impact the frequency of chronic seizures. However, these studies are limited in their clinical relevance as none of them determines the potential of blocking new neurons generated after the epileptogenic insult to alleviate the development of chronic seizures. Therefore, using a pilocarpine-induced SE model of mTLE in mice of either sex, we show that >4 weeks of continuous and concurrent ablation of seizure-induced neurogenesis after SE can reduce the formation of spontaneous recurrent seizures by 65%. We also found that blocking post-SE neurogenesis does not lead to long-term seizure reduction as the effect was observed only transiently for 10 d with >4 weeks of continuous and concurrent ablation of seizure-induced neurogenesis. Thus, these findings provide evidence that seizure-induced neurogenesis when adequately reduced in a clinically relevant time period has the potential to transiently suppress recurrent seizures, but additional mechanisms need to be targeted to permanently prevent epilepsy development. Consistent with morphological and electrophysiological studies suggesting aberrant adult-generated neurons contribute to epilepsy development, ablation of seizure-induced new neurons at the time of the initial insult reduces the frequency of recurrent seizures. In this study, we show that continuous targeting of post-insult new neurons in a therapeutically relevant time period reduces chronic seizures; however, this effect does not persist suggesting possible additional mechanisms.
内侧颞叶癫痫(MTLE)是成人中最常见的药物难治性癫痫形式,通常与海马生理学有关。使用 MTLE 的啮齿动物模型,包括我们实验室的许多研究表明,在称为癫痫持续状态(SE)的严重急性发作开始时产生的新神经元对于癫痫发生过程至关重要,并且通过遗传或药理学靶向诱导的神经发生可以影响慢性发作的频率。然而,由于这些研究都没有确定阻止癫痫发作后产生的新神经元的潜力以减轻慢性发作的发展,因此它们在临床相关性方面存在局限性。因此,我们使用匹鲁卡品诱导的 MTLE 雄性和雌性小鼠 SE 模型表明,SE 后持续和同时消融诱导的神经发生>4 周可以将自发性复发性癫痫发作的形成减少 65%。我们还发现,阻断 SE 后神经发生不会导致长期的癫痫发作减少,因为这种效果仅在 10 天内短暂观察到,而持续和同时消融诱导的神经发生>4 周。因此,这些发现提供了证据表明,在临床相关时间段内适当减少诱导的神经发生具有暂时抑制复发性癫痫发作的潜力,但需要针对其他机制来永久预防癫痫发作。与形态学和电生理学研究一致,这些研究表明异常的成年产生的神经元有助于癫痫发作的发展,在初始损伤时消融诱导的新神经元可降低复发性癫痫发作的频率。在这项研究中,我们表明在治疗相关时间内持续靶向新神经元可减少慢性癫痫发作;然而,这种效果并不持久,这表明可能存在其他机制。
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