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

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.

Lactate and pyruvate promote cellular stress resistance and longevity through ROS signaling

“…Lactate has been shown to play a role in enhancing neuronal survival 9,21 . These studies indicated that lactate promotes an increased ATP production and a better Ca 2+ buffering in a model of excitotoxicity.…”

Lactate: A Novel Signaling Molecule in Synaptic Plasticity and Drug Addiction

“…SFKs phosphorylate NMDAR subunits, which may sustain ERK activation following TrKB activation via Zn 2+ that influxes through NMDAR channels . A recent study also proved that lactate activates NR2B‐containing NMDARs, resulting in Ca 2+ influx and subsequent signaling cascade activation . We may infer that when we inject lactate in vivo, upregulation of NMDARs in certain brain regions will occur by virtue of the crucial role of NMDARs in synaptic plasticity, memory, and addiction.…”

“…NADH is mainly derived from lactate conversion into pyruvate via LDH in the presence of NAD + as the mediator of activating NR2B‐containing NMDARs. Subsequently, increased expression of ERK and a constellation of IEGs underlying synaptic plasticity and memory may stem from the elevation of intracellular Ca 2+ or NADH . Notably, NADH and NMDA can modulate the expression of nearly 65% and 70% of genes affected by lactate, respectively, suggesting that the lactate signaling predominantly exerts its function by activation of NMDAR .…”

“…Therefore, we can also consider NADH as one of the downstream molecules of lactate signaling. Notably, NADH can strengthen the activity of NMDARs due to their redox‐sensitive properties, leading to increased Ca 2+ influx . Moreover, the NAD + /NADH redox state is regarded as the key node between metabolism and signaling in the brain.…”

“…This new discovery implied that lactate is crucial in metabolism. Furthermore, recent studies indicate that l ‐lactate is thought to be a novel signaling molecule in tumor angiogenesis, muscle cells, neuroprotection, and immune and inflammatory responses, in addition to its metabolic function. l ‐Lactate is a pleiotropic molecule in many brain regions, playing an indispensable role in learning and memory as well.…”