• Conditional deletion of p21 in adult neural stem cells enhances hippocampal neurogenesis and working memory under physiological conditions.
• After traumatic brain injury, p21-deficient neural stem cells show an initial hyperactivation but lead to rapid depletion of the stem cell pool and impaired hippocampal function.
• p21 is a critical regulator of the balance between quiescence and activation of neural stem cells, essential for sustained neurogenic response post-injury.
• The study provides the first evidence of p21's role in modulating post-traumatic hippocampal neurogenesis, offering potential therapeutic targets for TBI.