The transfer of lactate, a product of aerobic glycolysis, from astrocytes to neurons was recently shown to be necessary for the establishment of long-term memory and for the maintenance of in vivo long-term potentiation. Here, we report that lactate induces the expression of plasticity genes such as Arc, c-Fos, and Zif268 in neurons. The action of lactate is mediated by the modulation of NMDA receptor activity and the downstream Erk1/2 signaling cascade, through a mechanism associated with changes in the cellular redox state. These observations unveil an unexpected role of lactate as a signaling molecule in addition to its role in energy metabolism and open a previously unidentified research avenue for the study of neuronal plasticity and memory.

Abstract

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.