Lateral Fluid Percussion Injury Impairs Hippocampal Synaptic Soluble N-Ethylmaleimide Sensitive Factor Attachment Protein Receptor Complex Formation.
Lateral Fluid Percussion Injury Impairs Hippocampal Synaptic Soluble N-Ethylmaleimide Sensitive Factor Attachment Protein Receptor Complex Formation.
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DOI：
10.3389/fneur.2017.00532
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发表时间：
2017
影响因子：
3.4
通讯作者：
Dixon CE
中科院分区：
文献类型：
--
作者：
Carlson SW;Henchir J;Dixon CE
创伤性脑损伤(TBI)和继发性损伤机制的激活与认知功能受损有关，正如在TBI患者和动物模型中观察到的那样，这种损害可以在初次损伤后持续数月甚至数年。在脑损伤的实验模型中，神经传递的损伤已经被很好地记录下来，但这种功能障碍背后的机制却知之甚少。可溶性N-乙基马来酰亚胺敏感因子附着蛋白受体(SNARE)复合体的形成促进了突触间隙中囊泡的对接和神经递质的释放。已发表的研究强调了减少陷阱复合体形成和神经递质释放障碍之间的直接联系。虽然在严重的局灶性脑损伤后已经描述了圈套复合体的改变，但尚不清楚在严重程度降低的模型中是否存在圈套复合体形成的缺陷。我们推测，侧向液压冲击伤(LFPI)减少了SNARE蛋白的丰度，损害了SNARE复合体的形成，并导致神经行为功能受损。为此，大鼠接受了LFPI或假损伤，并在损伤后3 周测试了急性运动表现和认知功能。LFPI致伤后1~5 出现运动功能障碍。经Morris水迷宫检测，LFP I后3 大鼠的空间获得和空间记忆能力明显受损。为了检测LFPI对损伤的海马区突触圈套复合体形成的影响，在损伤后1 周，产生一个单独的大鼠队列，并对大脑进行处理以评估海马区富含突触体的裂解产物。LFPI导致多种单体SNARE蛋白，包括VAMP2和α-突触核蛋白，以及SNARE复合体丰度显著降低。这项研究的发现与我们之前发表的观察结果一致，即海马区圈套复合体结构的损害可能导致与脑外伤相关的神经行为功能障碍。
Traumatic brain injury (TBI) and the activation of secondary injury mechanisms have been linked to impaired cognitive function, which, as observed in TBI patients and animal models, can persist for months and years following the initial injury. Impairments in neurotransmission have been well documented in experimental models of TBI, but the mechanisms underlying this dysfunction are poorly understood. Formation of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex facilitates vesicular docking and neurotransmitter release in the synaptic cleft. Published studies highlight a direct link between reduced SNARE complex formation and impairments in neurotransmitter release. While alterations in the SNARE complex have been described following severe focal TBI, it is not known if deficits in SNARE complex formation manifest in a model with reduced severity. We hypothesized that lateral fluid percussion injury (lFPI) reduces the abundance of SNARE proteins, impairs SNARE complex formation, and contributes to impaired neurobehavioral function. To this end, rats were subjected to lFPI or sham injury and tested for acute motor performance and cognitive function at 3 weeks post-injury. lFPI resulted in motor impairment between 1 and 5 days post-injury. Spatial acquisition and spatial memory, as assessed by the Morris water maze, were significantly impaired at 3 weeks after lFPI. To examine the effect of lFPI on synaptic SNARE complex formation in the injured hippocampus, a separate cohort of rats was generated and brains processed to evaluate hippocampal synaptosomal-enriched lysates at 1 week post-injury. lFPI resulted in a significant reduction in multiple monomeric SNARE proteins, including VAMP2, and α-synuclein, and SNARE complex abundance. The findings in this study are consistent with our previously published observations suggesting that impairments in hippocampal SNARE complex formation may contribute to neurobehavioral dysfunction associated with TBI.
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