Lactate shuttling links histone lactylation to adult hippocampal neurogenesis in mice.

Lactate has emerged as a central metabolic fuel and an important signaling molecule. Its availability participates in various brain functions. Although lactate homeostasis is vital for adult hippocampal neurogenesis and cognition, it is still unknown how shuttles lactate across the plasma membrane of neural stem cells (NSCs) to control their activity and neurogenic potential. In this study, we show that monocarboxylate transporter (MCT)1 and MCT2, respectively, control efflux and influx of lactate in the murine NSCs, thereby maintaining intracellular lactate homeostasis. Mechanistically, lactate shuttling links histone lactylation to govern NSC proliferation through MDM2-p53 signaling pathway. Notably, genetic ablation of MCT2 from NSCs or pharmacological inhibition of MDM2-P53 interaction prevents voluntary running-induced NSC proliferation in the murine adult hippocampus. Taken together, our findings demonstrate that lactate shuttling controls histone lactylation, which acts as a nexus for controlling adult hippocampal neurogenesis.