Shiri Zahra, Lévesque Maxime, Etter Guillaume, Manseau Frédéric, Williams Sylvain, Avoli Massimo
Montreal Neurological Institute, and Departments of Neurology & Neurosurgery and Physiology, McGill University, Montréal, Québec H3A 2B4, Canada, and.
Douglas Mental Health University Institute, McGill University, Montréal, Québec H4H 1R3, Canada.
J Neurosci. 2017 Mar 15;37(11):2999-3008. doi: 10.1523/JNEUROSCI.2244-16.2017. Epub 2017 Feb 16.
Despite many advances made in understanding the pathophysiology of epileptic disorders, seizures remain poorly controlled in approximately one-third of patients with mesial temporal lobe epilepsy. Here, we established the efficacy of cell type-specific low-frequency stimulation (LFS) in controlling ictogenesis in the mouse entorhinal cortex (EC) in an brain slice preparation. Specifically, we used 1 Hz optogenetic stimulation of calcium/calmodulin-dependent protein kinase II-positive principal cells as well as of parvalbumin- or somatostatin-positive interneurons to study the effects of such repetitive activation on epileptiform discharges induced by 4-aminopyridine. We found that 1 Hz stimulation of any of these cell types reduced the frequency and duration of ictal discharges in some trials, while completely blocking them in others. The field responses evoked by the stimulation of each cell type revealed that their duration and amplitude were higher when principal cells were targeted. Furthermore, following a short period of silence ranging from 67 to 135 s, ictal discharges were re-established with similar duration and frequency as before stimulation; however, this period of silence was longer following principal cell stimulation compared with parvalbumin- or somatostatin-positive interneuron stimulation. Our results show that LFS of either excitatory or inhibitory cell networks in EC are effective in controlling ictogenesis. Although optogenetic stimulation of either cell type significantly reduced the occurrence of ictal discharges, principal cell stimulation resulted in a more prolonged suppression of ictogenesis, and, thus, it may constitute a better approach for controlling seizures. Epilepsy is a neurological disorder characterized by an imbalance between excitation and inhibition leading to seizures. Many epileptic patients do not achieve adequate seizure control using antiepileptic drugs. Low-frequency stimulation (LFS) is an alternative tool for controlling epileptiform activity in these patients. However, despite the temporal and spatial control offered by LFS, such a procedure lacks cell specificity, which may limit its efficacy. Using an optogenetic approach, we report here that LFS of two interneuron subtypes and, even more so, of principal cells can reliably shorten or abolish seizures Our work suggests that targeted LFS may constitute a reliable means for controlling seizures in patients presenting with focal seizures.
尽管在理解癫痫性疾病的病理生理学方面取得了许多进展，但在大约三分之一的内侧颞叶癫痫患者中，癫痫发作仍难以得到有效控制。在此，我们在脑片制备中证实了细胞类型特异性低频刺激（LFS）在控制小鼠内嗅皮质（EC）癫痫发作产生方面的有效性。具体而言，我们使用1赫兹的光遗传学刺激，分别作用于钙/钙调蛋白依赖性蛋白激酶II阳性的主细胞以及小白蛋白或生长抑素阳性的中间神经元，以研究这种重复激活对4-氨基吡啶诱导的癫痫样放电的影响。我们发现，在某些实验中，对上述任何一种细胞类型进行1赫兹的刺激都能降低癫痫发作放电的频率和持续时间，而在其他实验中则能完全阻断癫痫发作放电。对每种细胞类型进行刺激所诱发的场反应表明，当以主细胞为靶点时，其持续时间和幅度更高。此外，在经历67至135秒的短暂沉默期后，癫痫发作放电会以与刺激前相似的持续时间和频率重新出现；然而，与小白蛋白或生长抑素阳性中间神经元刺激相比，主细胞刺激后的沉默期更长。我们的结果表明，对EC中兴奋性或抑制性细胞网络进行LFS可有效控制癫痫发作的产生。虽然对任何一种细胞类型进行光遗传学刺激都能显著减少癫痫发作放电的发生，但主细胞刺激能更持久地抑制癫痫发作的产生，因此，它可能是一种更好的控制癫痫发作的方法。癫痫是一种神经系统疾病，其特征是兴奋与抑制之间失衡，导致癫痫发作。许多癫痫患者使用抗癫痫药物无法实现充分的癫痫发作控制。低频刺激（LFS）是控制这些患者癫痫样活动的一种替代工具。然而，尽管LFS提供了时间和空间上的控制，但这种方法缺乏细胞特异性，这可能会限制其疗效。我们在此报告，通过光遗传学方法，对两种中间神经元亚型甚至主细胞进行LFS能够可靠地缩短或消除癫痫发作。我们的工作表明，靶向LFS可能是控制局灶性癫痫发作患者癫痫发作的可靠手段。
