Neutrophil depletion after subarachnoid hemorrhage improves memory via NMDA receptors.
Neutrophil depletion after subarachnoid hemorrhage improves memory via NMDA receptors.
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DOI：
10.1016/j.bbi.2016.02.007
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发表时间：
2016-05
期刊：
影响因子：
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通讯作者：
Ransohoff RM
中科院分区：
文献类型：
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作者：
Provencio JJ;Swank V;Lu H;Brunet S;Baltan S;Khapre RV;Seerapu H;Kokiko-Cochran ON;Lamb BT;Ransohoff RM
蛛网膜下腔出血（SAH）后的认知功能障碍是常见的和致残的。与血管痉挛相关的延迟恶化的患者可能有认知缺陷，特别是执行功能、语言和空间记忆的问题。在这里，我们报告神经生理和病理机制的行为缺陷的小鼠模型SAH。在空间记忆测试中，SAH动物在SAH后的第一周和一个月表现比假手术动物差，这表明了长期的损伤。在实验性出血后3至6天，小鼠表现出由于NMDA受体功能障碍而导致的晚期长时程增强（L-LTP）丧失。抑制先天免疫细胞活化可预防小鼠SAH后迟发性血管痉挛。因此，我们探讨了嗜中性粒细胞介导的先天性炎症对SAH后记忆缺陷的作用。SAH后3天中性粒细胞的消耗减轻了组织炎症，逆转了大脑中动脉的脑血管收缩，并在第6天挽救了L-LTP功能障碍。在短期和长期的空间记忆缺陷的改善，并与NMDA受体亚基组成的转变向记忆保留表型。这项工作支持进一步研究SAH后先天免疫抑制作为SAH预防性治疗的目标。
Cognitive deficits after aneurysmal subarachnoid hemorrhage (SAH) are common and disabling. Patients who experience delayed deterioration associated with vasospasm are likely to have cognitive deficits, particularly problems with executive function, verbal and spatial memory. Here, we report neurophysiological and pathological mechanisms underlying behavioral deficits in a murine model of SAH. On tests of spatial memory, animals with SAH performed worse than sham animals in the first week and one month after SAH suggesting a prolonged injury. Between three and six days after experimental hemorrhage, mice demonstrated loss of late long-term potentiation (L-LTP) due to dysfunction of the NMDA receptor. Suppression of innate immune cell activation prevents delayed vasospasm after murine SAH. We therefore explored the role of neutrophil-mediated innate inflammation on memory deficits after SAH. Depletion of neutrophils three days after SAH mitigates tissue inflammation, reverses cerebral vasoconstriction in the middle cerebral artery, and rescues L-LTP dysfunction at day 6. Spatial memory deficits in both the short and long-term are improved and associated with a shift of NMDA receptor subunit composition toward a memory sparing phenotype. This work supports further investigating suppression of innate immunity after SAH as a target for preventative therapies in SAH.