L-Lactate Regulates the Expression of Synaptic Plasticity and Neuroprotection Genes in Cortical Neurons: A Transcriptome Analysis

Abstract

Lactate, a product of aerobic glycolysis in astrocytes, is required for memory formation and consolidation, and has recently emerged as a signaling molecule for neurons and various cell types in peripheral tissues. In particular lactate stimulates mRNA expression of a few plasticity-related genes. Here, we describe a RNA-seq study that unravels genome-wide transcriptomic responses to this energy metabolite in cortical neurons. Our results show that mRNA expression of 20 immediate-early genes involved in the MAPK signaling pathway and in synaptic plasticity were increased by more than twofold following 1 h of lactate stimulation. This effect was dependent on NMDA receptor (NMDAR) activity since it was prevented by pre-treatment with MK-801. Comparison with published datasets showed that a significant proportion of genes modulated by lactate were similarly regulated by a stimulation protocol activating specifically synaptic NMDARs known to result in upregulation of pro-survival and downregulation of pro-death genes. Remarkably, transcriptional responses to lactate were reproduced by NADH (for 74 of the 113 genes, FDR < 0.05), suggesting a redox-dependent mechanism of action. Longer-term gene expression changes observed after 6 h of lactate treatment affected genes involved in regulating neuronal excitability and genes coding for proteins localized at synapses. Gene set enrichment analyses performed with ranked lists of expressed genes revealed effects on molecular functions involved in epigenetic modulation, and on processes relevant to sleep physiology and behavioral phenotypes such as anxiety and hyperactivity. Overall, these results strengthen the notion that lactate effectively regulates activity-dependent and synaptic genes, and highlight new signaling effects of lactate in plasticity and neuroprotection.

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

“…Moreover, activated Npas4 in the hippocampus and amygdala is engaged in fear memory and synaptic modulation . Recently, a transcriptome analysis of cortical neurons after application of lactate showed upregulation of Npas4 at the mRNA level . These observations led us to conjecture and validate that lactate promotes Npas4 expression during the process of memory formation despite limited studies.…”

“…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 . Notably, unlike other IEGs, Npas4 is selectively activated only by Ca 2+ ‐dependent depolarization instead of other inducers (such as several neurotrophic factors).…”

“…In addition, lactate is a mediator of NE signaling, which also increases the expression of learning‐associated molecules (i.e., Arc, pCaMKIIα) in the dorsal hippocampus after IA training. In particular, lactate could modulate the expression of Arrdc3 in a way that is independent of NMDAR . This gene is responsible for coding the arrestin domain‐containing protein 3, which is associated with intracellular β2‐ARs signaling in HER293 cells, indicating a close interaction between β2‐ARs signaling and lactate signaling in synaptic plasticity, learning and memory.…”

“…Intriguingly, some genes at the level of messenger RNA (mRNA), including the thioredoxininteracting protein (TXNIP), were found to become enriched in microglia after lactate treatment. [57] Furthermore, the inhibition of TXNIP-associated oxidative stress attenuated the cognitive impairment in a model of vascular dementia. [64] Considerable evidence indicates that microglia play a key role in synaptic plasticity, learning, and memory via the release of TNF-α in a model related to fear memory, [65] the production of lactate, and the modulation of structural plasticity such as LTD, synaptic 1.…”

“…Cocaine-induced CPP [11,48,53,54] In [11,40,44,45,48,56] In dorsal hippocampus, increased Arc protein [57][58][59][60] www.advancedsciencenews.com www.bioessays-journal.com pruning, axonal and dendritic growth. [66][67][68] Thus, combining all the aforementioned findings, it is conceivable that lactate acts as a signaling molecule in synaptic plasticity and memory via modulating microglia in a neuronal activity-dependent manner.…”