Persistent activation of microglia and NADPH oxidase [corrected] drive hippocampal dysfunction in experimental multiple sclerosis.
Persistent activation of microglia and NADPH oxidase [corrected] drive hippocampal dysfunction in experimental multiple sclerosis.
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DOI：
10.1038/srep20926
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发表时间：
2016-02-18
影响因子：
4.6
通讯作者：
Calabresi P
中科院分区：
文献类型：
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作者：
Di Filippo M;de Iure A;Giampà C;Chiasserini D;Tozzi A;Orvietani PL;Ghiglieri V;Tantucci M;Durante V;Quiroga-Varela A;Mancini A;Costa C;Sarchielli P;Fusco FR;Calabresi P
认知障碍在多发性硬化症（MS）中很常见。不幸的是，MS相关的认知功能障碍的突触和分子机制在很大程度上是未知的。我们探讨了实验性MS缓解期认知和突触海马功能障碍的存在和潜在机制。实验在运动缺陷的解决后，在慢性复发性实验性自身免疫性脑脊髓炎（EAE）MS模型中进行。在海马CA 1区进行免疫组织化学和膜片钳记录。洞板被用作认知/行为测试。在缓解期的实验MS，海马小胶质细胞的活化迹象，CA 1海马突触呈现受损的长时程增强（LTP）和空间测试的改变变得明显。EAE期间海马小胶质细胞的激活介导的突触和认知/行为改变。具体而言，LTP阻断被发现是由活性氧（ROS）产生酶烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶引起的。我们认为，在缓解期的实验MS小胶质细胞仍然激活，导致突触功能障碍介导的NADPH氧化酶。抑制小胶质细胞活化和NADPH氧化酶可能是预防与活动性神经炎症相关的神经可塑性损伤的一种有前景的策略，目的是改善认知并对抗MS疾病进展。
Cognitive impairment is common in multiple sclerosis (MS). Unfortunately, the synaptic and molecular mechanisms underlying MS-associated cognitive dysfunction are largely unknown. We explored the presence and the underlying mechanism of cognitive and synaptic hippocampal dysfunction during the remission phase of experimental MS. Experiments were performed in a chronic-relapsing experimental autoimmune encephalomyelitis (EAE) model of MS, after the resolution of motor deficits. Immunohistochemistry and patch-clamp recordings were performed in the CA1 hippocampal area. The hole-board was utilized as cognitive/behavioural test. In the remission phase of experimental MS, hippocampal microglial cells showed signs of activation, CA1 hippocampal synapses presented an impaired long-term potentiation (LTP) and an alteration of spatial tests became evident. The activation of hippocampal microglia mediated synaptic and cognitive/behavioural alterations during EAE. Specifically, LTP blockade was found to be caused by the reactive oxygen species (ROS)-producing enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. We suggest that in the remission phase of experimental MS microglia remains activated, causing synaptic dysfunctions mediated by NADPH oxidase. Inhibition of microglial activation and NADPH oxidase may represent a promising strategy to prevent neuroplasticity impairment associated with active neuro-inflammation, with the aim to improve cognition and counteract MS disease progression.