Autophagy is a cell-intrinsic driver of neural stem cell quiescence in hippocampal dentate gyrus development

Neurogenesis in the adult mammalian brain relies on the lifelong persistence of quiescent neural stem cell (NSC) reservoirs. Little is known about the mechanisms that lead to the initial establishment of NSC quiescence during development. Here, we show that protein aggregates and autophagy machinery components accumulate in quiescent NSCs and that pharmacological blockade of autophagy disrupts quiescence. Conversely, increasing autophagy through AMPK/ULK1 activation instructs the acquisition of the quiescent state. Selective ablation of Atg7, a critical gene for autophagosome formation, in hippocampal radial-glia like NSCs at early and late postnatal stages compromises the initial acquisition and maintenance of quiescence during the formation of the dentate gyrus SGZ niche. Therefore, we demonstrate that autophagy is cell-intrinsically required to establish radial glia-like NSC quiescence during hippocampal development. Our results uncover a fundamental role of autophagy in the transition of developmental NSCs into their dormant adult form, paving the way for studies directed at further understanding the mechanisms of stem cell niche formation and maintenance in the mammalian brain.