Elevated lactate suppresses neuronal firing in vivo and inhibits glucose metabolism in hippocampal slice cultures

Program in Neural and Behavioral Science, State University New York-Downstate Medical Center, Brooklyn, NY 11203, USA.
Brain Research (Impact Factor: 2.84). 11/2006; 1117(1):213-23. DOI: 10.1016/j.brainres.2006.07.107
Source: PubMed


Glucose is well accepted as the major fuel for neuronal activity, while it remains controversial whether lactate also supports neural activity. In hippocampal slice cultures, synaptic transmission supported by glucose was reversibly suppressed by lactate. To test whether lactate had a similar inhibitory effect in vivo, lactate was perfused into the hippocampi of unanesthetized rats while recording the firing of nearby pyramidal cells. Lactate perfusion suppressed pyramidal cell firing by 87.5+/-8.3% (n=6). Firing suppression was slow in onset and fully reversible and was associated with increased lactate concentration at the site of the recording electrode. In vivo suppression of neural activity by lactate occurred in the presence of glucose; therefore we tested whether suppression of neural firing was due to lactate interference with glucose metabolism. Competition between glucose and lactate was measured in hippocampal slice cultures. Lactate had no effect on glucose uptake. Lactate suppressed glucose oxidation when applied at an elevated, pathological concentration (10 mM), but not at its physiological concentration (1 mM). Pyruvate (10 mM) also inhibited glucose oxidation but was significantly less effective than lactate. The greater suppressive effect of lactate as compared to pyruvate suggests that alteration of the NAD(+)/NADH ratio underlies the suppression of glucose oxidation by lactate. ATP in slice culture was unchanged in glucose (1 mM), but significantly reduced in lactate (1 mM). ATP in slice culture was significantly increased by combination of glucose (1 mM) and lactate (1 mM). These data suggest that alteration of redox ratio underlies the suppression of neural discharge and glucose metabolism by lactate.

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    • "In any case, seal neurons survive incubation in lactate and remained active. This finding is surprising, since elevated lactate is known to suppress neuronal firing in vivo and in vitro (Gilbert et al., 2006). Indeed, this is what we observed in mouse neurons, although e.g. "
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    ABSTRACT: The brains of diving mammals are repeatedly exposed to hypoxic conditions during diving. Brain neurons of the hooded seal (Cystophora cristata) have been shown to be more hypoxia tolerant than those of mice, but the underlying mechanisms are not clear. Here we investigated the roles of different metabolic substrates for maintenance of neuronal activity and integrity, by comparing the in vitro spontaneous neuronal activity of brain slices from layer V of the visual cortex of hooded seals with those in mice (Mus musculus). Studies were conducted by manipulating the composition of the artificial cerebrospinal fluid (aCSF), containing either 10 mM glucose, or 20 mM lactate, or no external carbohydrate supply (aglycemia). Normoxic, hypoxic and ischemic conditions were applied. The lack of glucose or the application of lactate in the aCSF containing no glucose had little effect on the neuronal activity of seal neurons in either normoxia or hypoxia, while neurons from mice survived in hypoxia only few minutes regardless of the composition of the artificial cerebrospinal fluid. We propose that seal neurons have higher intrinsic energy stores. Indeed, we found about three times higher glycogen stores in the seal brain (∼4.1 ng per μg total protein in the seal cerebrum) than in the mouse brain. Notably, in aCSF containing no glucose, seal neurons can tolerate 20 mM lactate while in mouse neuronal activity vanished after few minutes even in normoxia. This can be considered as an adaptation to long dives, during which lactate accumulates in the blood.
    Full-text · Article · Jun 2014 · Neuroscience
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    • "So, as observed previously there are metabolic differences between structures of CNS [5] [10] [30]. Corroborating with these results, lactate is a preferential substrate for oxidation and it suppresses glucose oxidation by neurons in culture [14]. Age-related neurological disorders like Alzheimer's disease and endocrine diseases like Type 2 diabetes mellitus are conditions related to progressive accumulation of detrimental changes in the brain structure and function [2] [11]. "
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    ABSTRACT: Dehydroepiandrosterone (DHEA) prevents brain aging, enhances the cerebral metabolism and interacts with energy substrates. The interaction between lactate and DHEA on glucose uptake and lactate oxidation by various nervous structures was investigated and results demonstrate that the 2-(14)C-deoxiglucose (2-(14)C-Dglucose) uptake was stimulated by 10mM lactate in the hypothalamus and olfactory bulb, inhibited in the cerebral cortex and cerebellum, and unaffected in the hippocampus. We also show that, in both the cerebral cortex and hypothalamus, (14)C-lactate oxidation was higher than (14)C-glucose oxidation (p≤0.001), demonstrating a relevant role for lactate as energy substrate. The interaction of lactate and 10(-8)M DHEA was tested and, although DHEA had no significant effect on uptake in the cerebellum, hippocampus, or hypothalamus, 10(-8)M DHEA increased the 2-(14)C-Dglucose uptake in the cerebral cortex in the presence of lactate (p≤0.001), and in the olfactory bulb in the absence of lactate (p<0.05). However, DHEA had no significant effect on (14)C-lactate oxidation. We suggest that DHEA improves glucose uptake in specific conditions. Thus, DHEA may affect CNS metabolism and interact with lactate, which is the most important neuronal energy substrate, on glucose uptake.
    Full-text · Article · Dec 2011 · Neuroscience Letters
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    • "Lactate and ketones are weak acids that will transiently alter intracellular pH (see below). In addition, lactate alters the cytosolic redox state toward more reduced values in adult slices, and competes with glucose for NAD + , thus inhibiting its oxidation (Gilbert et al., 2006). "
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    ABSTRACT: Brain slices incubated with glucose have provided most of our knowledge on cellular, synaptic, and network driven mechanisms. It has been recently suggested that γ-aminobutyric acid (GABA) excites neonatal neurons in conventional glucose-perfused slices but not when ketone bodies metabolites, pyruvate, and/or lactate are added, suggesting that the excitatory actions of GABA are due to energy deprivation when glucose is the sole energy source. In this article, we review the vast number of studies that show that slices are not energy deprived in glucose-containing medium, and that addition of other energy substrates at physiologic concentrations does not alter the excitatory actions of GABA on neonatal neurons. In contrast, lactate, like other weak acids, can produce an intracellular acidification that will cause a reduction of intracellular chloride and a shift of GABA actions. The effects of high concentrations of lactate, and particularly of pyruvate (4-5 mm), as used are relevant primarily to pathologic conditions; these concentrations not being found in the brain in normal "control" conditions. Slices in glucose-containing medium may not be ideal, but additional energy substrates neither correspond to physiologic conditions nor alter GABA actions. In keeping with extensive observations in a wide range of animal species and brain structures, GABA depolarizes immature neurons and the reduction of the intracellular concentration of chloride ([Cl-]i) is a basic property of brain maturation that has been preserved throughout evolution. In addition, this developmental sequence has important clinical implications, notably concerning the higher incidence of seizures early in life and their long-lasting deleterious sequels. Immature neurons have difficulties exporting chloride that accumulates during seizures, leading to permanent increase of [Cl-]i that converts the inhibitory actions of GABA to excitatory and hampers the efficacy of GABA-acting antiepileptic drugs.
    Preview · Article · Jun 2011 · Epilepsia
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