Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 33; pp. 12228 - 12233
• Main Authors: Yang, Jiangyan, Ruchti, Evelyne, Petit, Jean-Marie, Jourdain, Pascal, Grenningloh, Gabriele, Allaman, Igor, Magistretti, Pierre J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 19-08-2014; National Acad Sciences
• Subjects: Animals; Astrocytes; Bioassays; Biological Sciences; Brain; Calcium; Calcium - metabolism; Cells, Cultured; Dehydrogenases; Energy metabolism; Gene expression; Gene Expression - drug effects; Lactates; Lactic Acid - pharmacology; Memory; Messenger RNA; Mice; N-Methylaspartate - metabolism; Neuronal Plasticity - genetics; Neurons; Neurons - metabolism; Plasticity; Rodents; Signal Transduction; astrocyte–neuron interaction; learning and memory; brain energy metabolism; astrocyte–neuron lactate shuttle
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1322912111

l -lactate is a product of aerobic glycolysis that can be used by neurons as an energy substrate. Here we report that in neurons l -lactate stimulates the expression of synaptic plasticity-related genes such as Arc, c-Fos, and Zif268 through a mechanism involving NMDA receptor activity and its downstream signaling cascade Erk1/2. l -lactate potentiates NMDA receptor-mediated currents and the ensuing increase in intracellular calcium. In parallel to this, l -lactate increases intracellular levels of NADH, thereby modulating the redox state of neurons. NADH mimics all of the effects of l -lactate on NMDA signaling, pointing to NADH increase as a primary mediator of l -lactate effects. The induction of plasticity genes is observed both in mouse primary neurons in culture and in vivo in the mouse sensory-motor cortex. These results provide insights for the understanding of the molecular mechanisms underlying the critical role of astrocyte-derived l -lactate in long-term memory and long-term potentiation in vivo. This set of data reveals a previously unidentified action of l -lactate as a signaling molecule for neuronal plasticity.