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  • As previously discussed even though

    2022-05-13

    As previously discussed, even though glucose is the major fuel of the brain, neuronal cells may use alternative fuels such as ketone bodies in metabolically challenging situations in which glucose availability is limited [6]. Ketogenesis takes place mainly in the liver, although astrocytes can also synthesize ketone bodies [47], [48] and supply them to neurons [49]. Therefore, the existence of an astrocyte-neuron ketone body shuttle could explain how the DBIBB adapts to metabolic challenges by switching to alternative sources of energy [50]. Of note, recent evidence has shown a role for oligodendrocytes in supporting axonal energy metabolism by supplying glycolytic-derived lactate to neurons [51], [52]. Later studies suggested that NMDA receptor activation in oligodendrocytes would promote glucose uptake and glycolysis to supply lactate to neurons, thus contributing to preserve axonal energy homeostasis [53]. Future investigation will help delineate the metabolic network established by different cell populations in the brain, and how they contribute to shape neuronal excitability.
    Extracellular effects of metabolites on neuronal excitability The regulation of metabolic communication between brain cells is highly complex and constitutes an active field of research. The fact that metabolites flow between cells opens up the possibility that they may have physiological roles that they impart from the extracellular milieu. For example, the role of ATP and its derivatives as signaling molecules in the brain and neurotransmitters has been the subject of intense investigation [reviewed in 54]. Above we discussed the role of lactate-derived ATP as a modulator of neuronal activity [34]. Ketone bodies may also contribute to set the pace for neuronal firing rates through its actions on the adenosine A1 receptors [9]. More recently, the identification of select G-protein coupled receptors (GPCRs) located on the plasma membrane that respond to nutrients has opened up new potential mechanisms of crosstalk between metabolism and other physiological processes [55]. To cite some examples, the G-protein coupled hydroxycarboxylic acid receptors 1 (HCA1 or GPR81) and 2 (HCA2 or GPR109a) can be activated by L-lactate and β-D-hydroxybutyrate, respectively [55]. GPR81 is expressed at high levels in the brain, especially in the excitatory synapses in hippocampus and cerebellum [56]. Neuronal GPR81 is functionally active, as its stimulation leads to decreased cAMP levels, which suggests that it DBIBB could act as a modulator of neuronal activity [56]. In fact, L-lactate-dependent activation of GPR81 reduces the frequency of spontaneous spikes in intracellular calcium mobilization in cultured mouse cortical neurons, suggesting that L-lactate reduces spontaneous neuronal firing [57]. Altogether, these results indicate that extracellular L-lactate may contribute directly to modulate neuronal excitability through GPR81 independently of its function as an energy substrate. The role of the receptor for β-hydroxybutyrate, HCA2/GPR109a, as a direct modulator of neuronal excitability has not been explored. GPR109a is expressed predominantly in adipose tissue and immune cells, including macrophages, monocytes, neutrophils and dendritic cells, and recent evidence points to an anti-inflammatory role [58]. GPR109a expression in the brain, however, is not so high, and according to different studies, seems to be restricted to select areas and cell types. It contributes to coordinate endocrine homeostasis in the hypothalamus by regulating the synthesis of growth hormone-releasing hormone [59]. Another study showed that GPR109a expression is upregulated in the Substantia nigra of patients suffering from Parkinson's Disease [60]. Albeit the majority of cells expressing GPR109a were identified as microglial cells, some neuronal cells also showed expression of GPR109a, even in healthy subjects [60]. Upregulation of GPR109a in microglial cells was also observed in an experimental rat model of Parkinson´s Disease, and its stimulation with β-hydroxybutyrate reduced microglial activation and concomitant inflammation both in vitro and in vivo[61]. However, the expression of GPR109a in neurons was not analyzed in the latter study.