Graduate Program in Neuroscience, Georgia Health Sciences University, Augusta, Georgia, USA.
Glia. 2012 Nov;60(11):1709-20. doi: 10.1002/glia.22390. Epub 2012 Jul 20.
Spreading depolarizations are a key event in the pathophysiology of stroke, resulting in rapid dendritic beading, which represents acute damage to synaptic circuitry. The impact of spreading depolarizations on the real-time injury of astrocytes during ischemia is less clear. We used simultaneous in vivo 2-photon imaging and electrophysiological recordings in adult mouse somatosensory cortex to examine spreading depolarization-induced astroglial structural changes concurrently with signs of neuronal injury in the early periods of focal and global ischemia. Astrocytes in the metabolically compromised ischemic penumbra-like area showed a long lasting swelling response to spontaneous spreading depolarizations despite rapid dendritic recovery in a photothrombotic occlusion model of focal stroke. Astroglial swelling was often facilitated by recurrent depolarizations and the magnitude of swelling strongly correlated with the total duration of depolarization. In contrast, spreading depolarization-induced astroglial swelling was transient in normoxic healthy tissue. In a model of transient global ischemia, the occurrence of a single spreading depolarization elicited by a bilateral common carotid artery occlusion coincided with astroglial swelling alongside dendritic beading. With immediate reperfusion, dendritic beading subsides. Astroglial swelling was either transient during short ischemic periods distinguished by a short-lasting spreading depolarization, or persistent during severe ischemia characterized by a long-lasting depolarization with the ultraslow negative voltage component. We propose that persistent astroglial swelling is initiated and exacerbated during spreading depolarization in brain tissue with moderate to severe energy deficits, disrupting astroglial maintenance of normal homeostatic function thus contributing to the negative outcome of ischemic stroke as astrocytes fail to provide neuronal support.
扩布性去极化是中风病理生理学中的一个关键事件，导致树突迅速珠化，这代表着突触回路的急性损伤。扩布性去极化对缺血期间星形胶质细胞实时损伤的影响尚不清楚。我们使用成年小鼠体感皮层的体内双光子成像和电生理记录，同时检查了局灶性和全脑缺血早期扩布性去极化引起的星形胶质细胞结构变化以及神经元损伤的迹象。在光血栓性局灶性中风模型中，代谢受损的缺血半影区中的星形胶质细胞对自发性扩布性去极化表现出持久的肿胀反应，尽管树突迅速恢复。星形胶质细胞肿胀通常由反复去极化促进，并且肿胀幅度与去极化总持续时间强烈相关。相比之下，在正常含氧健康组织中，扩布性去极化诱导的星形胶质细胞肿胀是短暂的。在短暂性全脑缺血模型中，双侧颈总动脉闭塞引起的单次扩布性去极化的发生与树突珠化和星形胶质细胞肿胀同时发生。立即再灌注时，树突珠化消退。在短暂的缺血期间，星形胶质细胞肿胀是短暂的，其特征是短暂的扩布性去极化；或者在严重的缺血期间，星形胶质细胞肿胀是持久的，其特征是具有超慢负电压成分的持久去极化。我们提出，在中度至重度能量不足的脑组织中，持续的扩布性去极化会引发并加剧持久的星形胶质细胞肿胀，破坏星形胶质细胞维持正常的稳态功能，从而导致缺血性中风的不良结局，因为星形胶质细胞无法为神经元提供支持。
