Sustained Notch activation depletes adult neural stem cells and impairs cognitive function

Abstract

Notch signaling is essential for maintenance of neural stem cells (NSCs) and proper brain function. To investigate the functional consequences of sustained Notch activation, we generated a spatiotemporally controlled, tetracycline-inducible transgenic mouse model Nestin-CreER, ROSA26-rtTA, TRE-loxP-DsRed2-loxP-c-Myc-NICD. In this model, sustained NICD overexpression promotes rapid consuming cell division that drives NSCs to terminally differentiate rather than undergo self-renewal. This mechanism led to severe depletion of the NSC pool in both the subependymal zone (SEZ) and subgranular zone of the hippocampal dentate gyrus. In the SEZ, NSC depletion was paradoxically accompanied by an increased supply of newborn neurons to the olfactory bulb, but these cells did not contribute to better function. NICD overexpression mice showed significant impairments in spatial and emotional memory, and social discrimination. Collectively, sustained Notch activation in Nestin-lineage cells induces an imbalance in NSC maintenance, resulting in exhaustion of NSC pools and integration of non-functional cells, ultimately altering both olfactory and hippocampal-dependent behaviors.