Microglial depletion after brain injury prolongs inflammation and impairs brain repair, adult neurogenesis and pro-regenerative signaling

Abstract

The adult zebrafish brain, unlike mammals, has a remarkable regenerative capacity. Although inflammation in part hinders regeneration in mammals, it is necessary for zebrafish brain repair. Microglia are resident brain immune cells that regulate the inflammatory response. To explore the microglial role in repair, we used liposomal clodronate or colony stimulating factor-1 receptor (csf1r) inhibitor to suppress microglia after brain injury, and also examined regeneration in two genetic mutant lines that lack microglia. We found that microglial ablation impaired telencephalic regeneration after injury. Microglial suppression attenuated cell proliferation at the intermediate progenitor cell amplification stage of neurogenesis. Notably, the loss of microglia impaired phospho-Stat3 (signal transducer and activator of transcription 3) and ß-Catenin signaling after injury. Furthermore, the ectopic activation of Stat3 and ß-Catenin rescued neurogenesis defects caused by microglial loss. Microglial suppression also prolonged the post-injury inflammatory phase characterized by neutrophil accumulation, likely hindering the resolution of inflammation. These findings reveal specific roles of microglia and inflammatory signaling during zebrafish telencephalic regeneration that should advance strategies to improve mammalian brain repair.