Bumetanide increases microglia-interneuron contact following traumatic brain injury
Bumetanide increases microglia-interneuron contact following traumatic brain injury
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DOI：
10.1101/2022.06.03.494659
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发表时间：
2022-06
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通讯作者：
M. Tessier;Marta Saez Garcia;Emmanuelle Goubert;L. Tian;F. Molinari;Edith Blasco;J. Laurin;F. Guillemot;C. Hübner;C. Pellegrino;C. Rivera
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作者：
M. Tessier;Marta Saez Garcia;Emmanuelle Goubert;L. Tian;F. Molinari;Edith Blasco;J. Laurin;F. Guillemot;C. Hübner;C. Pellegrino;C. Rivera
目的 Na-K-Cl 协同转运蛋白 (NKCC1) 抑制剂布美他尼对许多神经系统疾病的病理生理学具有显着的积极作用。在这里，我们研究了布美他尼是否可以通过调节星形胶质细胞和小胶质细胞的激活来影响创伤后认知衰退和炎症过程。方法 受控皮质受影响 (CCI) 动物在 CCI 后第一周接受布美他尼治疗。使用免疫化学、流式细胞术、免疫分析和体内成像来研究星形胶质细胞和小胶质细胞的形态和表型以及成人神经发生。 CCI 后 1 个月进行遥测脑电图和认知行为测试。结果布美他尼可防止 CCI 诱导的海马神经发生减少和小清蛋白阳性中间神经元丢失。删除星形胶质细胞中的 NKCC1 既不能挽救中间神经元，也不能促进神经发生。有趣的是，布美他尼通过诱导 CCI 后 3 天的 M1 样表型极化和 CCI 后 7 天的 M2 样表型极化，对小胶质细胞活化产生强烈影响。布美他尼增加小胶质细胞脑源性神经营养因子 (BDNF) 的表达以及与小清蛋白中间神经元的相互作用。 CCI 后一个月，布美他尼的早期治疗改善了工作记忆和情景记忆，并使 θ 带振荡正常化。在这里，我们公开了一种布美他尼神经保护作用的新机制，该机制是通过小胶质细胞活化动力学加速介导的，导致CCI后小白蛋白中间神经元存活率增加，这可能是由于小胶质细胞BDNF表达增加以及与中间神经元的接触所致。中间神经元的挽救可能会使环境中的γ-氨基丁酸（GABA）正常化，从而保留成体神经发生过程，并有助于布美他尼介导的认知能力改善。
Objective The Na-K-Cl cotransporter (NKCC1) inhibitor bumetanide has prominent positive effects on the pathophysiology of many neurological disorders. Here we studied whether bumetanide could influence post-traumatic cognitive decline and inflammatory processes by regulating astrocyte and microglia activation. Method Controlled cortical impacted (CCI) animals were treated with bumetanide during the first post-CCI week. Immunochemistry, flow cytometry, immunoassay, and in vivo imaging were used to study astrocytic and microglial morphology and phenotype as well as adult neurogenesis. Telemetric electroencephalograms and cognitive behavioral test were performed at one-month post CCI. Results Bumetanide prevented CCI-induced decrease in hippocampal neurogenesis and parvalbumin positive interneuron loss. Deletion of NKCC1 in astrocytes neither rescued interneurons nor promote neurogenesis. Interestingly, bumetanide had a strong effect on microglial activation by inducing polarization towards the M1-like phenotype 3 days post-CCI and the M2-like phenotype 7 days post-CCI. Bumetanide increased microglial Brain-derived neurotrophic factor (BDNF) expression and interaction with parvalbumin interneurons. The early treatment with bumetanide resulted in improvements in working and episodic memory, one-month post-CCI, as well as the normalization of theta band oscillations. Interpretation Here, we disclose a novel mechanism for the neuroprotective action of bumetanide mediated by an acceleration of microglial activation dynamics that leads to an increase of parvalbumin interneuron survival following CCI, possibly resulting from increased microglial BDNF expression and contact with interneurons. Salvage of interneurons may normalize ambient gamma-aminobutyric acid (GABA) resulting in the preservation of adult neurogenesis processes as well as contributing to bumetanide-mediated improvement of cognitive performance.