Jourdain, P.Rothenfusser, K.Ben-Adiba, C.Allaman, I.Marquet, P.Magistretti, P. J.2018-12-132018-12-132018-12-132018-09-0710.1038/s41598-018-31534-yhttps://infoscience.epfl.ch/handle/20.500.14299/152378WOS:000444024100007L-Lactate is a positive modulator of NMDAR-mediated signaling resulting in plasticity gene induction and memory consolidation. However, L-Lactate is also able to protect neurons against excito-toxic NMDAR activity, an indication of a mitigating action of L-Lactate on NMDA signaling. In this study, we provide experimental evidence that resolves this apparent paradox. Transient co-application of glutamate/glycine (1 mu M/100 mu M; 2 min) in primary cultures of mouse cortical neurons triggers a NMDA-dependent Ca2+ signal positively modulated by L-Lactate (10 mM) or DTT (1 mM) but decreased by Pyruvate (10 mM). This L-Lactate and DTT-induced potentiation is blocked by Ifenprodil (2 mu M), a specific blocker of NMDARs containing NR2B sub-units. In contrast, co-application of glutamate/glycine (1 mM/100 mu M; 2 min) elicits a NMDAR-dependent excitotoxic death in 49% of neurons. L-Lactate and Pyruvate significantly reduce this rate of cell death processes (respectively to 23% and 9%) while DTT has no effect (54% of neuronal death). This L-Lactate-induced neuroprotection is blocked by carbenoxolone and glibenclamide, respectively blockers of pannexins and K-ATP. In conclusion, our results show that L-Lactate is involved in two distinct and independent pathways defined as NMDAR-mediated potentiation pathway (or NADH pathway) and a neuroprotective pathway (or Pyruvate/ATP pathway), the prevalence of each one depending on the strength of the glutamatergic stimulus.Multidisciplinary SciencesScience & Technology - Other Topicsdigital holographic microscopysynaptically released glutamatehippocampal synapsescerebral-ischemiaenergy-metabolismneuronal-activityrefractive-indexcell morphometrycalcium-releaseca2+ releasetext::journal::journal article::research article