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Bumetanide induces post-traumatic microglia-interneuron contact to promote neurogenesis and recovery.
journal contributionposted on 2023-10-05, 09:46 authored by Marine Tessier, Marta Saez Garcia, Emmanuelle Goubert, Edith Blasco, Amandine Consumi, Benoit Dehapiot, Li Tian, Florence Molinari, Jerome Laurin, François Guillemot, Christian A Hübner, Christophe Pellegrino, Claudio Rivera
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 for elucidating the role of Nkcc1 has been mainly focused on neurons. 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 behavioral 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 of 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 one 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 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.