Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, United States of America.
Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, United States of America; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland.
Neurobiol Dis. 2023 Apr;179:106058. doi: 10.1016/j.nbd.2023.106058. Epub 2023 Mar 1.
The epilepsies are a diverse spectrum of disease states characterized by spontaneous seizures and associated comorbidities. Neuron-focused perspectives have yielded an array of widely used anti-seizure medications and are able to explain some, but not all, of the imbalance of excitation and inhibition which manifests itself as spontaneous seizures. Furthermore, the rate of pharmacoresistant epilepsy remains high despite the regular approval of novel anti-seizure medications. Gaining a more complete understanding of the processes that turn a healthy brain into an epileptic brain (epileptogenesis) as well as the processes which generate individual seizures (ictogenesis) may necessitate broadening our focus to other cell types. As will be detailed in this review, astrocytes augment neuronal activity at the level of individual neurons in the form of gliotransmission and the tripartite synapse. Under normal conditions, astrocytes are essential to the maintenance of blood-brain barrier integrity and remediation of inflammation and oxidative stress, but in epilepsy these functions are impaired. Epilepsy results in disruptions in the way astrocytes relate to each other by gap junctions which has important implications for ion and water homeostasis. In their activated state, astrocytes contribute to imbalances in neuronal excitability due to their decreased capacity to take up and metabolize glutamate and an increased capacity to metabolize adenosine. Furthermore, due to their increased adenosine metabolism, activated astrocytes may contribute to DNA hypermethylation and other epigenetic changes that underly epileptogenesis. Lastly, we will explore the potential explanatory power of these changes in astrocyte function in detail in the specific context of the comorbid occurrence of epilepsy and Alzheimer's disease and the disruption in sleep-wake regulation associated with both conditions.
癫痫是一种具有自发性癫痫发作和相关合并症的疾病谱。以神经元为重点的观点产生了一系列广泛使用的抗癫痫药物，能够解释一些但不是全部导致自发性癫痫发作的兴奋和抑制失衡。此外，尽管新型抗癫痫药物定期获得批准，但药物抵抗性癫痫的发生率仍然很高。更全面地了解将健康大脑转变为癫痫大脑（癫痫发生）的过程以及产生个体癫痫发作（癫痫发生）的过程可能需要将我们的关注点扩大到其他细胞类型。正如本综述中详细介绍的那样，星形胶质细胞以神经传递和三突触的形式增强单个神经元的神经元活动。在正常情况下，星形胶质细胞对于维持血脑屏障完整性和修复炎症和氧化应激至关重要，但在癫痫中，这些功能受到损害。癫痫导致星形胶质细胞通过缝隙连接相互作用的方式发生中断，这对离子和水稳态具有重要意义。在激活状态下，星形胶质细胞由于摄取和代谢谷氨酸的能力降低以及代谢腺苷的能力增加，导致神经元兴奋性失衡。此外，由于腺苷代谢增加，激活的星形胶质细胞可能有助于 DNA 过度甲基化和其他表观遗传变化，这些变化是癫痫发生的基础。最后，我们将详细探讨星形胶质细胞功能这些变化在癫痫和阿尔茨海默病合并发生以及与这两种情况相关的睡眠-觉醒调节中断的具体背景下的解释力。
