Principal Investigator: Prof Pierre Magistretti

Poster Presenter: Hubert Fiumelli



Mechanism of NMDA receptor potentiation by lactate


Astrocyte-derived lactate fuels the high-energy demands of neurons and acts as a signal promoting synaptic plasticity and memory consolidation. Lactate regulates neuronal excitability and modulates gene expression related to synaptic plasticity and neuroprotection, but its mode of action is uncertain. Using patch-clamp recordings in cultured cortical neurons, we found that lactate enhances, in a calcium-dependent manner, the amplitude and inactivation time constant of NMDA receptor currents (INMDAR) evoked by brief applications of glutamate and glycine. Agonists of the HCAR1/gpr81 receptor did not reproduce these effects, while monocarboxylate transporters and lactate dehydrogenase inhibitors prevented the lactate-mediated increases in INMDAR amplitude. Intracellular infusion of specific CaMKII peptide inhibitors also abolished the potentiation of peak INMDAR responses by lactate, and manipulating the intracellular and extracellular redox balance additively influenced the INMDAR, indicating the existence of a mechanism that requires the entry of lactate into neurons, redox changes via lactate oxidation to pyruvate, and involvement of CaMKII. Quantitative immunoprecipitation showed that lactate increased the binding of CaMKII to GluN2B, whereas interfering with the binding between CaMKII and GluN2B prevented the potentiation of INMDAR responses by lactate. Proximity ligation assays between GluN2B and the postsynaptic density marker PSD-95 revealed that lactate induced an accumulation of GluN2B in dendritic spines, an effect that was prevented by a CaMKII peptide inhibitor. Together, these findings establish a mechanistic link between astrocyte-derived lactate and the CaMKII- and NMDAR-dependent synaptic plasticity.