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Vaccari-Cardoso, B.;  Antipina, M.;  Teschemacher, A.G.;  Kasparov, S. Lactate-Mediated Signaling in the Brain. Encyclopedia. Available online: https://encyclopedia.pub/entry/40130 (accessed on 26 October 2024).
Vaccari-Cardoso B,  Antipina M,  Teschemacher AG,  Kasparov S. Lactate-Mediated Signaling in the Brain. Encyclopedia. Available at: https://encyclopedia.pub/entry/40130. Accessed October 26, 2024.
Vaccari-Cardoso, Barbara, Maria Antipina, Anja G. Teschemacher, Sergey Kasparov. "Lactate-Mediated Signaling in the Brain" Encyclopedia, https://encyclopedia.pub/entry/40130 (accessed October 26, 2024).
Vaccari-Cardoso, B.,  Antipina, M.,  Teschemacher, A.G., & Kasparov, S. (2023, January 12). Lactate-Mediated Signaling in the Brain. In Encyclopedia. https://encyclopedia.pub/entry/40130
Vaccari-Cardoso, Barbara, et al. "Lactate-Mediated Signaling in the Brain." Encyclopedia. Web. 12 January, 2023.
Lactate-Mediated Signaling in the Brain
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This entry is adapted from the peer-reviewed paper 10.3390/brainsci13010049

Lactate is a universal metabolite produced and released by all cells in the body. Traditionally it was viewed as energy currency that is generated from pyruvate at the end of the glycolytic pathway and sent into the extracellular space for other cells to take up and consume. In the brain, such a mechanism was postulated to operate between astrocytes and neurons many years ago. 

lactate astrocyte signaling

1. Introduction

Following glycolysis, Lac is generated from pyruvate by lactate dehydrogenase (LDH), an enzyme that operates in both directions, using NADH to reduce pyruvate into Lac (Figure 1). Even though LDH isoforms differ in their interconversion rates, both LDHA and LDHB are thought to establish an equivalent pyruvate-Lac equilibrium under steady-state conditions [1]. As such, Lac cannot be metabolized any further. It is either released to the extracellular space and shared with other cells, or is reconverted by LDH to pyruvate which then can enter the TCA cycle in the mitochondria.
Brainsci 13 00049 g001 550
Figure 1. Interconversion of lactic and pyruvic acid is mediated by LDH and recovers NAD+ used in glycolysis. Glucose for glycolysis is imported from the periphery or/and recruited from glycogen under conditions that stimulate glycogenolysis.
All Lac release mechanisms identified so far are gradient-dependent. These involve monocarboxylate transporters (MCT) of which isoforms 1 and 4 are predominantly expressed by astrocytes and MCT2 is mainly found in neurons [2]. In addition, Lac release from astrocytes through connexin hemichannels has been implied by a number of publications [3][4]. A Lac-permeable ion channel which could be activated by depolarization and positively modulated by Lac has also been described [5] and further routes may potentially exist. In the brain, Lac is released by both neurons and astrocytes but it is well established that astrocytes produce and release more Lac than neurons [6]. This creates a gradient of Lac from astrocytes towards the extracellular space and neurons [7][8]. As can be seen from the following, some of the proposed mechanisms require Lac entry into neurons in the vicinity, others postulate that Lac acts on receptors located on the cell surface.

2. Mechanisms Which are Attributed to Lac Entry into Target Neurons

The concept of Lac being passed on between different cell types is well established for peripheral tissues [9]. For the brain, the hypothesis of an analogous Lac shuttle operating between astrocytes and neurons was proposed decades ago [10], originally, as a mechanism to subsidize neurons with energy under conditions of high metabolic demand such as periods of active firing of action potentials [11][12]. Perhaps one of the more contentious aspects of the shuttle hypothesis is the question of why astrocytic Lac, once transferred into neurons, should be used in preference to glucose for ATP generation. The relative importance of astrocytic Lac as a source of neuronal ATP is still controversial.

Many studies argue for the importance of Lac as the source of energy but the actual link between the availability of ATP and the end-point effects is usually assumed, rather than demonstrated directly. Typically the effects of MCT block or LDH block or drugs which interfere with Lac mobilisation in astrocytes are used as arguments to support the caloric role of Lac Many of the approaches used in these studies have limitations. 

Overall, the body of studies which support the use of Lac for energy generation in preference to glucose is substantial, for example [13][14], but is it always preferred to glucose and why? A recently published study from the L. Venance group offers an essential clue which may explain the existing controversies [15]. Here, experiments in vitro, in vivo and mathematical modelling are combined to carefully dissect which conditions favor the utilization of glucose vs Lac. The authors used two types of protocols, for example, in vitro, a high frequency (100 Hz) 5 x theta burst stimulation that should require more energy for generation of LTP and, for comparison, spike timing–dependent plasticity (STDP) where frequency of stimulation is relatively low. Both forms of plasticity are dependent on NMDA receptors. It was shown that while the high frequency LTP requires Lac provision, STDP does not. In vivo the authors use a simpler novel object recognition task where the rat needs to detect one new object and compare it with a more complex test (object in place) where several objects have been moved in the arena. Here the simple test is not sensitive to oxamate while the more challenging test is, again pointing to the preferential use of Lac in situations of high energy demand. These experiments are matched by mathematical modelling. This study demonstrates that, while Lac (provided largely by astrocytes) is required to support synaptic activity when the energy consumption is high, the conditions of the experiment are paramount. 

Another line of argument relates effects of Lac to modulation of to NAD+/NADH ratio which could lead to potentiation of NMDA receptors. These effects were noted when high concentrations of Lac (2.5 mM - 20 mM) were used [16][17]. Some studies aimed to trigger release of Lac from astrocytes by optogenetic or chemogenetic activation of astrocytes in hippocampus, assuming that the released Lac will trigger effects via NMDA receptor modulation or energy provision to neurones [16][17] [18][19][20]. These studies are interesting and raise a very important set of questions. How can an activated astrocyte or a group of astrocytes modulate a specific memory trace, given that each astrocyte contacts numerous neurons, potentially many thousands of synapses? Moreover, Lac almost certainly can spread between astrocytes via gap junctions, which would further diffuse the signal within the network. Can astrocytic modulation be targeted to individual synapses which are contacted by distinct end feet of the same astrocyte? Or is the role of astrocytes to provide a wide-scale change in the extracellular concentration of metabolites such as Lac, ATP, glutamate, etc. that results in more general network modulation? Under which physiological conditions could one expect the activation of large pools of astrocytes in the hippocampus and what would be the mechanism? If, as per [21][22], such activation occurs, would that elicit amnesia covering the preceding 24 hours? These are exciting questions and, clearly, a lot of work still needs to be done to explain how the stimulation of astrocytes affects memory formation and retention and whether there may be specific mechanisms for compartmentalization of intra- and inter-cellular Lac signaling in astrocytes  [20][23][24][25][26][27][28][29][30].

3. Cell Surface Receptor-Mediated Signaling by Lac in the Brain

It is well established that Lac can affect cell function via cell surface G-protein coupled receptors (GPCR) without the need to access the cytoplasm (Figure 2). Lac has its cognate receptor, registered by IUPHAR (https://www.guidetopharmacology.org/ (accessed on 1 December 2022)) as HCA1 (previously known as Lactate receptor 1, LACR1, GPR81, GPR104). It is encoded by the gene HCAR1. The physiological role of HCA1 is best established in adipocytes where it inhibits lipolysis via the Gi-protein signaling cascade [31]. In neurons, Gi signaling is characteristically associated with the inhibition of action potential activity and transmitter release. Lac has very low potency on HCA1. In the original publication, EC50 for Lac for HCA from different species are listed between 3.7–6.9 mM ([32], Table 1). This is not surprising because, in the periphery, Lac levels in plasma are typically at several millimoles and increase prominently during exercise. Hence, HCA1 sensitivity matches physiological Lac levels (for further discussion see [33]). In the brain, however, according to most sources, average extracellular Lac concentrations do not exceed 1.5–2 mM. While it cannot be excluded that Lac can be more concentrated in microdomains, higher average concentrations of Lac have been reported in pathophysiological situations such as during hypoxia or seizures [33].
Brainsci 13 00049 g003 550
Figure 2. Summary of putative Lac receptor-mediated signaling mechanisms in brain cells. Lac transported into the cell can be metabolised and/or influence gene expression, e.g., via NMDA receptor modulation or ERK pathway activation. Increased ATP levels may inhibit KATP channel activity and decrease cell excitability. Lac may also act via surface GPCR to stimulate or inhibit neurones. The effects of acidification caused by protons co-imported via MCT require clarification. Researchers also hypothesise that Lac can be converted into Lac-Phe in the brain, the implications of which have yet to be discovered. Black arrows—stimulatory action; red lines—inhibitory. AC—adenylate cyclase; NA—noradrenaline; NDRG3, ERK(P)—phosphorylation of extracellular signal-regulated kinases; mit—mitochondria. Modified from [33].
The group of J-Y Chatton have published several studies reporting inhibitory effects of Lac on mouse neurons via HCA1 [34][35][36][37]. Using both wild-type and HCA1 knock-out mice, the authors report in their studies the inhibitory effects of Lac and 3-chloro-5-hydroxybenzoic acid (3Cl-HBA), an agonist of HCA1, on neurons in patch-clamp and calcium imaging experiments. Decreases in miniature excitatory postsynaptic potential (EPSC) frequency were also observed. These inhibitory effects of Lac on neurons are explained by the activation of the canonical Gi-protein signaling pathways by Lac [37]. Moreover, the hippocampal neurons that are modulated by HCA1 were suggested to be excitatory, not inhibitory, since they did not counter-stain for GAD67 [35]. In the latter study, additional experiments were carried out on acute slices from human patients where a reduction in spontaneous EPSC frequency after the application of 3Cl-HBA was found. Overall, the take-home message from this body of work is that neurons in various parts of rodent and human brain express HCA1, and HCA1 activation by Lac inhibits neuronal activity by reducing excitability and via presynaptic mechanisms. While these results are interesting and potentially very significant, Lac-mediated inhibition of excitatory neurons in many areas of the brain is quite difficult to reconcile with many of the experiments where the astrocytic release of Lac is seen to facilitate learning and memory. The balance in a physiological context between the support of actively firing neurons metabolically or via potentiation of NMDA currents by Lac and their inhibition via HCA1 needs to be considered further. During strenuous physical exercise, plasma concentrations of Lac rise dramatically and Lac can travel from plasma into the brain, thus increasing central Lac levels [38]. Brain Lac concentrations also rise during arousal [39]. If HCA1-mediated inhibition was operational within the physiological range of Lac concentrations, this should result in a shutdown of cortical and hippocampal networks, which clearly does not occur. This suggests that the key questions relate to the relevant concentrations of both Lac and 3Cl-HBA in modulating neuronal activity.
A study by Ordenes and colleagues offers a completely different view of the potential mechanism by which HCA1 can modulate neurons [40]. They studied the arcuate nucleus (ARC) where proopiomelanocortin (POMC) neurons synthesize the anorexigenic neuropeptide α-MSH derived from the POMC transcript. Brain slices used in this study were perfused with ACSF containing 1 mM glucose. This factor (concentration of glucose in the media) can be quite important in many analyses on cultured cells and slices but is not often discussed or considered. Of note, the vast majority of slice studies use solutions with 5 or even 10 mM glucose. This specific study found that ~60% of POMC neurons were activated by 15 mM Lac. Surprisingly, 15 mM D-lactate and 15 mM glucose also activated POMC neurons, but 4-CIN did not prevent the Lac effect, suggesting an extracellular target. The HCA1 agonist 3Cl-HBA (40 µM) also depolarized POMC neurons, and its action could be blocked by pertussis toxin, confirming the involvement of Gi-protein signaling. Altogether these results point to a role of HCA1, however, the authors could not find HCAR1 transcripts in single-cell transcriptomes of POMC neurons. Instead, using immunohistochemistry, they demonstrate that HCA1 is expressed by local astrocytes. According to the paper, activation of HCA1 on astrocytes leads to a paradoxical increase in astrocytic intracellular Ca2+. While Ca2+ increase seems an unexpected effect following activation of a Gi-coupled receptor, it has been reported for astrocytes in other studies [41][42][43]. The authors speculate that this could lead to the release of excitatory gliotransmitters, possibly glutamate, and by this mechanism, POMC neurons may be stimulated by Lac and 3Cl-HBA. With respect to the coupling of HCA1, the current situation is not entirely clear and it is possible that some of the effects are mediated by the βγ complex or another type of Gα subunits, which is not uncommon for G-protein coupled receptors. In addition, the authors argue that if Lac is taken up by POMC neurons, it would lead to increased ATP production, closure of ATP-sensitive K+ channels (KATP), and depolarization, although the paper does not appear to contain direct evidence in support of this suggestion [40].
Finally, researchers consider studies from their own group which also indicate that the brain operates with Lac-sensitive GPCR, but ones distinct from HCA1. Researchers reviewed some of the relevant studies in [33] and now only briefly summarize the current state of play. In 2014, their group demonstrated a link between astrocytes local to a specific subset of noradrenergic neurons in the Locus coeruleus (LC; [44]). Researchers concluded that astrocyte-derived Lac stimulates the release of noradrenaline from LC neurons and activates these neurons via a cAMP-dependent signaling pathway. Multiple experiments in that study indicated that Lac does not need to enter LC neurons and that the most logical explanation for these effects was the existence of another, yet uncharacterized, GPCR-mediated signaling pathway which can be recruited by Lac. LC neurons are specialized and different from glutamatergic neurons studied in most other papers. They are rather unique in their morphology and physiology and project all across the central nervous system. Activation of LC is associated with central arousal and active brain states [45][46][47]. Hence, the excitatory effect of Lac on these cells could possibly provide a link between overall brain activity and attention or positive motivation responses and reflect a mechanism by which LC activation by salient stimuli may be amplified to orchestrate generalized cortical desynchronization. Interestingly, researchers later observed that Lac can also activate another group of noradrenergic neurons in the rostral ventro-lateral medulla that is responsible for activating the sympathetic nervous system, consistent with an autonomic arousal response [48]. Researchers postulated that this effect is mediated by a yet unknown GPCR which has been termed Lac receptor x (or “LLRx”) and is expected to operate via a cAMP-mediated mechanism. Over the years, researchers have made multiple attempts to identify LLRx and learn more about it but with limited success. For instance, researchers characterized in a later study its activation by compounds derived from Lac [33].
Apart from HCA1, which is a Gi-protein coupled receptor and inhibits cAMP production, there are at least two GPCRs sensitive to Lac and known to couple to Gs-proteins, thus being able to raise cAMP. These are the olfactory receptor OR51E2, which is expressed in several other tissues outside of olfactory epithelium, such as the prostate. Researchers could not confirm the expression of OR51E2 in LC neurons and its pharmacological characteristics do not match what researchers know about LLRx [33]. By serendipity, researchers found that the proton receptor GPR4, previously known as GPR19 [49], can be modulated by Lac [50]. GPR4 can probably couple to various G-proteins, but its main signaling partner is Gs and, when stimulated, GPR4 leads to profound increases in cAMP [49][50]. GPR4 is expressed by endothelium around the body, including the brain and also by some subsets of neurons, but not the LC neurons. Researchers found that Lac negatively modulates GPR4 and reduces proton-induced cAMP responses [50]. Hence, the characteristics of this GPCR are not consistent with the elusive LLRx but, nevertheless, modulation of GPR4 by Lac could be important for some aspects of brain function.
Researchers undertook a screening effort, analyzed a range of orphan GPCRs that are expressed by LC neurons and found one receptor that could be a viable candidate for further experimentation [33]. In a luminescence assay, the application of Lac within the range of concentrations which researchers consider physiological (less than 5 mM) to HEK cells expressing GPR137 resulted in highly significant increases in cAMP. 5 mM of Lac elevated luminescence to ~175% relative to control. Moreover, 0.4 mM D-lactate antagonized the effect of 2 mM Lac, consistent with researchers' previously reported observations [44]. In terms of its sequence and splicing pattern, GPR137 is not a typical GPCR. While the typical number of 7 transmembrane regions has been predicted for its amino acid sequence (www.proteinatlas.org (accessed on 1 December 2022), it shares little homology with other GPCRs and its coupling to G-proteins has not been confirmed (IUPHAR guidetopharmacology.org). Nevertheless, its expression is verified by multiple databases, and it has been preferentially localized to the lysosomal compartment (Ensemble, Genecards, NCBI). The potential physiological roles of GPR137 are still little understood. According to in situ hybridization data in the Allen Brain Atlas, there is a widespread expression of the GPR137 transcript in mouse brain (http://mouse.brain-map.org/experiment/show/75651149 (accessed on 1 December 2022). While apparently present in human and mouse, in rat it may not even exist as a full-length protein (https://www.guidetopharmacology.org/ (accessed on 1 December 2022). Researchers believe that the effect of Lac via this receptor should be investigated further.
Similarly, researchers also found that in cells transfected to express GPR180, Lac could reduce cAMP [33]. While recently it has been shown that GPR180 is not a GPCR but, instead, a component of the TGFβ signaling complex, it may still be an interesting candidate to mediate some Lac effects in the brain [51].
An interesting and entirely unexpected avenue might have been opened by a recent discovery of biological activity of the Lac metabolite N-lactoyl-phenylalanine (Lac-Phe). This product of conjugation of Lac with phenylalanine is formed in the periphery when Lac levels are increased by exercise in mice, humans and racehorses, and can suppress food consumption [52]. This effect strongly suggests a central site of action although the study does not address this possibility. A speculation, that may merit further investigation is that, if Lac in the brain could also be converted into Lac-Phe, some of the central effects previously associated with Lac could actually be mediated by Lac-Phe or a similar metabolite.

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Subjects: Physiology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Barbara Vaccari-Cardoso
,
Maria Antipina
,
Anja G. Teschemacher
,
Sergey Kasparov
View Times: 831
Revisions: 4 times (View History)
Update Date: 13 Jan 2023
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