Tamoxifen exerts direct and microglia‐mediated effects preventing neuroinflammatory changes in the adult mouse hippocampal neurogenic niche

Abstract Tamoxifen‐inducible systems are widely used in research to control Cre‐mediated gene deletion in genetically modified animals. Beyond Cre activation, tamoxifen also exerts off‐target effects, whose consequences are still poorly addressed. Here, we investigated the impact of tamoxifen on lipopolysaccharide (LPS)‐induced neuroinflammatory responses, focusing on the neurogenic activity in the adult mouse dentate gyrus. We demonstrated that a four‐day LPS treatment led to an increase in microglia, astrocytes and radial glial cells with concomitant reduction of newborn neurons. These effects were counteracted by a two‐day tamoxifen pre‐treatment. Through selective microglia depletion, we elucidated that both LPS and tamoxifen influenced astrogliogenesis via microglia mediated mechanisms, while the effects on neurogenesis persisted even in a microglia‐depleted environment. Notably, changes in radial glial cells resulted from a combination of microglia‐dependent and ‐independent mechanisms. Overall, our data reveal that tamoxifen treatment per se does not alter the balance between adult neurogenesis and astrogliogenesis but does modulate cellular responses to inflammatory stimuli exerting a protective role within the adult hippocampal neurogenic niche.