Lactate enhances the NMDA receptor response by altering the intracellular redox state

Lactate acts as an energy substrate and a signaling molecule to modulate neuronal functions such as excitability, plasticity and long-term memory formation. Lactate is known to regulate the NMDA receptor (NMDAR) activity through a NADH-dependent pathway. This effect leads to a modulation of synaptic plasticity-related gene expression. We have now observed that lactate potentiates NMDAR response by increasing the peak NMDAR currents (I_NMDAR) and prolonging the decay time. These effects are sensitive to Ifenprodil (GluN2B antagonist), but not to PEAQX (GluN2A antagonist), suggesting that lactate increases the contribution of GluN2B subunit to the increased NMDAR response. The lactate-mediated increase in peak I_NMDAR requires uptake of lactate into neurons and is blocked by inhibitors of lactate dehydrogenase, an enzyme that converts lactate into pyruvate with a concomitant rise in the NADH/NAD⁺ ratio. Compared to intracellular delivery, bath application of reducing agent Dithiothreitol (DTT) enhanced the lactate-mediated increase in peak I_NMDAR in an additive manner. In contrast, both bath and intracellular applications of the oxidizing agent 5,5-dithiobis-(2-nitrobenzoic acid) (DTNB) decrease the I_NMDAR potentiation by lactate. These indicate that lactate may act intracellularly through a redox-mediated regulation of NMDAR function. Using a thiol-trapping approach, we found that both n-acetylcysteine amide (NACA) and lactate increase the levels of reduced thiol (-SH) in GluN2B, possibly through modification of intracellular redox state. Lactate enhancement of the NMDAR response is dependent on Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), a kinase known to bind to synaptic NMDAR. Lactate-induced I_NMDAR potentiation is abolished when the binding of GluN2B to CaMKII kinase domain is impaired. Together, these results suggest that lactate boosts synaptic plasticity through a redox-mediated regulation of GluN2B-containing NMDAR which may promotes the interaction of CaMKII with GluN2B to further enhance the NMDAR response.