Yi Jae-Hyuk, Hoover Rachel, McIntosh Tracy K, Hazell Alan S
Department of Medicine, Hôpital Saint-Luc, University of Montreal, Montreal, Quebec, Canada.
J Neurotrauma. 2006 Jan;23(1):86-96. doi: 10.1089/neu.2006.23.86.
Alteration of excitatory neurotransmission is a key feature of traumatic brain injury (TBI) in which extracellular glutamate levels rise. Although increased synaptic release of glutamate occurs at the injury site, the precise mechanism is unclear. Complexin I and complexin II constitute a family of cytosolic proteins involved in the regulation of neurotransmitter release, competing with the chaperone protein alpha-SNAP (soluble N-ethylmaleimide-sensitive factor-attachment protein) for binding to the synaptic vesicle protein synaptobrevin as well as the synaptic membrane proteins SNAP-25 and syntaxin, which together form the SNAP receptor (SNARE) complex. Complexin I is predominantly a marker of axosomatic (inhibitory) synapses, whereas complexin II mainly labels axodendritic and axospinous synapses, the majority of which are excitatory. In order to examine the role of these proteins in TBI, we have studied levels of both complexins in the injured hemisphere by immunoblotting over a time period ranging from 6 h to 7 days following lateral fluid-percussion brain injury in the rat. Transient increases in the levels of complexin I and complexin II proteins were detected in the injured cerebral cortex 6 h following TBI. This increase was followed by a decrease of complexin I in the injured cortex and hippocampus, and a decrease in both complexins in the injured thalamus region at day 3 and day 7 post-injury. The early, transient increase in the injured cortex was completely blocked by N-acetylcysteine (NAC) administered 5 min following trauma, suggesting an involvement of oxidative stress. Neuronal loss was also reduced in the injured hemisphere with post-TBI NAC treatment. Our findings suggest a dysregulation of both inhibitory and excitatory neurotransmission following traumatic injury that is responsive to antioxidant treatment. These alterations in complexin levels may also play an important role in neuronal cell loss following TBI, and thus contribute to the pathophysiology of cerebral damage following brain injury.
兴奋性神经传递的改变是创伤性脑损伤（TBI）的一个关键特征，在这种损伤中细胞外谷氨酸水平会升高。虽然在损伤部位谷氨酸的突触释放增加，但其确切机制尚不清楚。复合体I和复合体II构成了一类胞质蛋白家族，参与神经递质释放的调节，它们与伴侣蛋白α-SNAP（可溶性N-乙基马来酰亚胺敏感因子附着蛋白）竞争，以结合突触囊泡蛋白突触结合蛋白以及突触膜蛋白SNAP-25和 syntaxin，这些蛋白共同形成SNAP受体（SNARE）复合体。复合体I主要是轴体（抑制性）突触的标志物，而复合体II主要标记轴树突和轴棘突触，其中大多数是兴奋性的。为了研究这些蛋白在TBI中的作用，我们通过免疫印迹法研究了大鼠侧方流体冲击性脑损伤后6小时至7天内损伤半球中这两种复合体的水平。TBI后6小时在损伤的大脑皮层中检测到复合体I和复合体II蛋白水平的短暂升高。这种升高之后，损伤皮层和海马中的复合体I减少，在损伤后第3天和第7天，损伤丘脑区域的两种复合体均减少。损伤皮层中早期的短暂升高在创伤后5分钟给予N-乙酰半胱氨酸（NAC）后被完全阻断，这表明氧化应激参与其中。TBI后给予NAC治疗也减少了损伤半球中的神经元损失。我们的研究结果表明，创伤性损伤后抑制性和兴奋性神经传递均失调，对抗氧化治疗有反应。复合体水平的这些改变也可能在TBI后的神经元细胞损失中起重要作用，从而导致脑损伤后脑损伤的病理生理学变化。
