布美他尼
中间神经元
神经发生
小胶质细胞
神经科学
帕尔瓦布明
海马结构
神经保护
海马体
抑制性突触后电位
生物
医学
内科学
炎症
离子运输机
遗传学
膜
作者
M. Tessier,Marta Saez Garcia,Emmanuelle Goubert,Edith Blasco,Amandine Consumi,Benoît Dehapiot,Kadri Seppa,Florence Molinari,Jérôme Laurin,François Guillemot,Christian A. Hübner,Christophe Pellegrino,Claudio Rivera
出处
期刊:Brain
[Oxford University Press]
日期:2023-04-21
卷期号:146 (10): 4247-4261
被引量:2
标识
DOI:10.1093/brain/awad132
摘要
Abstract Although the Na-K-Cl cotransporter (NKCC1) inhibitor bumetanide has prominent positive effects on the pathophysiology of many neurological disorders, the mechanism of action is obscure. Attention paid to elucidating the role of Nkcc1 has mainly been focused on neurons, but recent single cell mRNA sequencing analysis has demonstrated that the major cellular populations expressing NKCC1 in the cortex are non-neuronal. We used a combination of conditional transgenic animals, in vivo electrophysiology, two-photon imaging, cognitive behavioural tests and flow cytometry to investigate the role of Nkcc1 inhibition by bumetanide in a mouse model of controlled cortical impact (CCI). Here, we found that bumetanide rescues parvalbumin-positive interneurons by increasing interneuron-microglia contacts shortly after injury. The longitudinal phenotypic changes in microglia were significantly modified by bumetanide, including an increase in the expression of microglial-derived BDNF. These effects were accompanied by the prevention of CCI-induced decrease in hippocampal neurogenesis. Treatment with bumetanide during the first week post-CCI resulted in significant recovery of working and episodic memory as well as changes in theta band oscillations 1 month later. These results disclose a novel mechanism for the neuroprotective action of bumetanide mediated by an acceleration of microglial activation dynamics that leads to an increase in parvalbumin interneuron survival following CCI, possibly resulting from increased microglial BDNF expression and contact with interneurons. Salvage of interneurons may normalize ambient GABA, resulting in the preservation of adult neurogenesis processes as well as contributing to bumetanide-mediated improvement of cognitive performance.
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