Editors' ChoiceNeuroscience

From lactate to antidepressant

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Science Signaling  08 Jun 2021:
Vol. 14, Issue 686, eabj8007
DOI: 10.1126/scisignal.abj8007

The metabolism of lactic acid has antidepressant effects in mice.

Depression causes major disability and is challenging to treat. Stress can trigger depression, whereas exercise can counteract stress and has beneficial effects on patients. One product of exercise, endorphins, is often credited for these benefits. Carrard et al. found that the metabolism of a different product of exercise, lactate, has antidepressant effects by stimulating the proliferation of neurons in the hippocampus. In a mouse model of depression, administration of the stress hormone corticosterone suppressed the proliferation and survival of adult hippocampal neural progenitor cells (NPCs) and induced depression-like behaviors in the mice. However, subsequent intraperitoneal injections of lactate (daily for three weeks) reversed NPC loss and improved behavior. Notably, these reversals were not seen with the administration of pyruvate, the oxidized product of lactate metabolism. Instead, the authors identified that one beneficial mediator was NADH, an antioxidant that is generated through the oxidation of lactate to pyruvate by lactate dehydrogenase and which is implicated in promoting the activity of neuronal NMDA receptors. NADH administration, like that of lactate, suppressed the production of reactive oxygen species in NPCs and reversed NPC loss caused by corticosterone. Chemical inhibition of neurogenesis suppressed the antidepressant effects of lactate, indicating that the neurogenic effect was key. These findings may have implications for treatment strategies and expand our understanding of the connections between energy metabolism, neuroscience, and depression.

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