Dual action of L-Lactate on the activity of NR2B-containing NMDA receptors: from potentiation to neuroprotection

P Jourdain,I Allaman,P Marquet,P J Magistretti,K Rothenfusser,C Ben-Adiba

doi:10.1038/s41598-018-31534-y

Abstract

L-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 μM/100 μM; 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 μM), a specific blocker of NMDARs containing NR2B sub-units. In contrast, co-application of glutamate/glycine (1 mM/100 μM; 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 KATP. 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.

Highlights

NMDA receptors (NMDARs) are glutamate-gated cation channels with high calcium permeability
We sought to determine whether the opening of NR2B-containing NMDARs alone could explain such an increase in Ca2+ response duration in L-Lactate condition or whether other activation cascades intervene in the generation of this Ca2+ signal
In recent years two apparently contrasting effects of L-Lactate have been demonstrated: the potentiation of the NMDAR activity resulting in plasticity gene expression[6] and the neuroprotective effect against excessive NMDAR activity[14], the question being how the same molecule can potentiate some positive effects of glutamate while inhibiting others, both involving NMDARs? In this report, we show that this apparent paradox is explained by the efficiency of L-Lactate to potentiate NMDARs for a certain activation window corresponding to a subthreshold concentration of glutamate

Summary

Introduction

NMDA receptors (NMDARs) are glutamate-gated cation channels with high calcium permeability. NMDARs by L-Lactate[6] associated with neuroplasticity seems hard to reconcile with the neuroprotective action of L-Lactate against NMDAR-mediated excito-toxicity[14] This apparent discrepancy is reinforced by the fact that the positive modulation of NMDAR activity by L-Lactate is associated with an increase in the redox potential of neurons as determined by the NADH/NAD+ ratio[6]. Such redox conditions are known to increase the activity of NMDARs16,17 to a point where they may cause glutamate-evoked neurotoxicity[18]. The mitigation of the [Ca2+]i increases elicited by excito-toxic concentrations of glutamate, are shared by Pyruvate and involve the formation of ATP, consistent with the previously described neuroprotective effect of L-Lactate and Pyruvate[14]

Methods

Results

Conclusion