Bumetanide increases microglia-interneuron contact following traumatic brain injury

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. ### Competing Interest Statement The authors have declared no competing interest.