Alcoreza Oscar B, Patel Dipan C, Tewari Bhanu P, Sontheimer Harald
Glial Biology in Health, Disease, and Cancer Center, Fralin Biomedical Research Institute, Virginia Tech Carilion, Roanoke, VA, United States.
School of Medicine, Virginia Tech Carilion, Roanoke, VA, United States.
Front Neurol. 2021 Mar 22;12:652159. doi: 10.3389/fneur.2021.652159. eCollection 2021.
Given the important functions that glutamate serves in excitatory neurotransmission, understanding the regulation of glutamate in physiological and pathological states is critical to devising novel therapies to treat epilepsy. Exclusive expression of pyruvate carboxylase and glutamine synthetase in astrocytes positions astrocytes as essential regulators of glutamate in the central nervous system (CNS). Additionally, astrocytes can significantly alter the volume of the extracellular space (ECS) in the CNS due to their expression of the bi-directional water channel, aquaporin-4, which are enriched at perivascular endfeet. Rapid ECS shrinkage has been observed following epileptiform activity and can inherently concentrate ions and neurotransmitters including glutamate. This review highlights our emerging knowledge on the various potential contributions of astrocytes to epilepsy, particularly supporting the notion that astrocytes may be involved in seizure initiation via failure of homeostatic responses that lead to increased ambient glutamate. We also review the mechanisms whereby ambient glutamate can influence neuronal excitability, including via generation of the glutamate receptor subunit GluN2B-mediated slow inward currents, as well as indirectly affect neuronal excitability via actions on metabotropic glutamate receptors that can potentiate GluN2B currents and influence neuronal glutamate release probabilities. Additionally, we discuss evidence for upregulation of System , a cystine/glutamate antiporter expressed on astrocytes, in epileptic tissue and changes in expression patterns of glutamate receptors.
鉴于谷氨酸在兴奋性神经传递中发挥的重要作用，了解其在生理和病理状态下的调节机制对于设计治疗癫痫的新疗法至关重要。丙酮酸羧化酶和谷氨酰胺合成酶在星形胶质细胞中的特异性表达，使星形胶质细胞成为中枢神经系统（CNS）中谷氨酸的重要调节因子。此外，由于星形胶质细胞表达双向水通道水通道蛋白-4，且在血管周围终足处富集，它们可显著改变中枢神经系统细胞外空间（ECS）的容积。癫痫样活动后可观察到ECS迅速收缩，这会使包括谷氨酸在内的离子和神经递质固有地浓缩。本综述重点介绍了我们对星形胶质细胞在癫痫中的各种潜在作用的新认识，特别支持星形胶质细胞可能通过稳态反应失败导致细胞外谷氨酸增加而参与癫痫发作起始的观点。我们还综述了细胞外谷氨酸影响神经元兴奋性的机制，包括通过生成谷氨酸受体亚基GluN2B介导的缓慢内向电流，以及通过作用于代谢型谷氨酸受体间接影响神经元兴奋性，后者可增强GluN2B电流并影响神经元谷氨酸释放概率。此外，我们讨论了癫痫组织中星形胶质细胞上表达的胱氨酸/谷氨酸反向转运体系统 上调的证据以及谷氨酸受体表达模式的变化。
