PDF(Pubmed)
Abstract：
Reactive astrocytes are associated with neuroinflammation and cognitive decline in diverse neuropathologies; however, the underlying mechanisms are unclear. We used optogenetic and chemogenetic tools to identify the crucial roles of the hippocampal CA1 astrocytes in cognitive decline. Our results showed that repeated optogenetic stimulation of the hippocampal CA1 astrocytes induced cognitive impairment in mice and decreased synaptic long-term potentiation (LTP), which was accompanied by the appearance of inflammatory astrocytes. Mechanistic studies conducted using knockout animal models and hippocampal neuronal cultures showed that lipocalin-2 (LCN2), derived from reactive astrocytes, mediated neuroinflammation and induced cognitive impairment by decreasing the LTP through the reduction of neuronal NMDA receptors. Sustained chemogenetic stimulation of hippocampal astrocytes provided similar results. Conversely, these phenomena were attenuated by a metabolic inhibitor of astrocytes. Fiber photometry using GCaMP revealed a high level of hippocampal astrocyte activation in the neuroinflammation model. Our findings suggest that reactive astrocytes in the hippocampus are sufficient and required to induce cognitive decline through LCN2 release and synaptic modulation. This abnormal glial-neuron interaction may contribute to the pathogenesis of cognitive disturbances in neuroinflammation-associated brain conditions.
摘要：
反应性星形胶质细胞与各种神经病理中的神经炎症和认知功能下降有关；然而，潜在机制尚不清楚.我们使用光遗传学和化学遗传学工具来确定海马CA1星形胶质细胞在认知衰退中的关键作用。我们的结果表明，反复光遗传学刺激海马CA1星形胶质细胞可引起小鼠认知障碍，并降低突触长时程增强（LTP），伴随着炎性星形胶质细胞的出现。使用敲除动物模型和海马神经元培养物进行的机制研究表明，脂质运载蛋白2（LCN2），来自反应性星形胶质细胞，通过减少神经元NMDA受体来降低LTP介导的神经炎症和诱导的认知障碍。海马星形胶质细胞的持续化学遗传刺激提供了类似的结果。相反，这些现象被星形胶质细胞的代谢抑制剂减弱。使用GCaMP的纤维光度法显示在神经炎症模型中高水平的海马星形胶质细胞活化。我们的发现表明，海马中的反应性星形胶质细胞足以通过LCN2释放和突触调节来诱导认知下降。这种异常的神经胶质-神经元相互作用可能有助于神经炎症相关脑部疾病中认知障碍的发病机理。
