Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism

In the paper

“the focus will be on neurons which comprise most (∼80–90%) of the energy demand of the brain (Attwell and Laughlin, 2001; Yu et al., 2017).”

What the sources say

• Not checked yetcites Attwell and Laughlin, 2001 source
• Not checked yetcites Yu et al., 2017

In the paper

“For instance, if the unstimulated tissue in the periphery or even within the stimulated region is capable of oxidative metabolism of the excess lactate (Madsen et al., 1999; Gandhi et al., 2009), then including the contribution from this tissue will normalize the OGI.”

What the sources say

• Not checked yetcites Madsen et al., 1999 source
• Not checked yetcites Gandhi et al., 2009 source

In the paper

“Second, OGI may be exaggerated or suppressed depending on how the stimulated region is defined.”

In the paper

“This is supported by measurements showing local elevation of brain lactate levels with stimulation (Korf and de Boer, 1990; Hu and Wilson, 1997; Mazuel et al., 2017) and even lactate export from the brain (e.g., Duffy et al., 1975, with stronger stimuli such as epileptic seizures).”

What the sources say

• Not checked yetcites Duffy et al., 1975 source

In the paper

“Experiments in support of the ANLS often argue for its feasibility rather than providing direct evidence that it occurs.”

In the paper

“This is supported by measurements showing local elevation of brain lactate levels with stimulation (Korf and de Boer, 1990; Hu and Wilson, 1997; Mazuel et al., 2017) and even lactate export from the brain (e.g., Duffy et al., 1975, with stronger stimuli such as epileptic seizures).”

What the sources say

• Not checked yetcites Korf and de Boer, 1990
• Not checked yetcites Hu and Wilson, 1997
• Not checked yetcites Mazuel et al., 2017 source

In the paper

“Finally, consistent with stress contributing to the reduced OGI, β-adrenergic blockade by propranolol reduces or eliminates the stimulation-induced change in OGI (Dienel and Cruz, 2016).”

What the sources say

• Not checked yetcites Dienel and Cruz, 2016

In the paper

“In contrast, the brain’s tricarboxylic acid (TCA) cycle is fed mainly by metabolites derived from circulating glucose, with relatively little intermediate mixing of lactate from the circulation.”

What the sources say

• Not checked yetcites Hui et al., 2017 source

In the paper

“The best estimates for the oxygen–glucose index (OGI; OGI = CMRO2/CMRglc) in the resting brain is around ∼5.5 in gray matter (Clarke and Sokoloff, 1994; Hyder et al., 2013), very close to the ideal stoichiometry of 6.”

What the sources say

• Not checked yetcites Clarke and Sokoloff, 1994
• Not checked yetcites Hyder et al., 2013 source

In the paper

“The overall OGI is reduced from the near-stoichiometric values down to ∼5 (Madsen et al., 1999).”

What the sources say

• Not checked yetcites Madsen et al., 1999 source

In the paper

“For the resting brain, the rates of glycolysis and oxphos appear well matched, with the cerebral metabolic rates (CMRs) of glucose and oxygen corresponding with nearly complete oxidation of glucose to pyruvate to CO2.”

In the paper

“But the increase in oxygen utilization is much less, on the order of 5%, indicating that the additional glucose consumption is not stoichiometrically matched by oxygen but rather that glucose is metabolized nonoxidatively by glycolysis without oxphos.”

In the paper

“Second, the measurement conditions in some studies could be perturbed by excessive stress in the experimental subjects (meaning that the preconditions for reduced OGI may not be so simple as enhanced activity); furthermore, stimulus strength can have a nonlinear effect on the metabolic response mechanisms.”

In the paper

“The drop in OGI during brain stimulation was the first indication of some transient uncoupling of glycolysis and oxphos in the brain (Fox et al., 1988).”

What the sources say

• Not checked yetcites Fox et al., 1988 source

In the paper

“However, the use of pure lactate as an alternative fuel, rather than a redox-balanced mixture of lactate and pyruvate, abnormally elevates the low cytosolic NADH redox ratio in neurons (seen in vitro by Hung et al. [2011] and Mongeon et al. [2016] as well as in vivo by Díaz-García et al. [2017]); this decreases the rate of neuronal glycolysis in a way that would not represent the normal effect in”

In the paper

“At the protein level, cultured neurons and astrocytes have substantial expression of the glycolytic enzymes (Fig. 1, right); here, the pattern is somewhat reversed, with ∼1.5- to threefold lower expression in neurons for some of the enzymes (the outliers are the MCTs, which are required for the ANLS but are 40-fold lower in neurons).”

What the sources say

• Not checked yetcites Fig. 1

In the paper

“Baseline accumulation of the analogue into astrocytes and neurons was similar; upon whisker stimulation in anesthetized rats, uptake into both cell types tended to increase, though only significantly for astrocytes (Chuquet et al., 2010).”

What the sources say

• Not checked yetcites Chuquet et al., 2010 source

In the paper

“and recent single-cell transcriptomics studies show roughly equal expression of the two isoforms in neurons (Fig. 1).”

What the sources say

• Not checked yetcites Fig. 1

In the paper

“At the protein level, cultured neurons and astrocytes have substantial expression of the glycolytic enzymes (Fig. 1, right); here, the pattern is somewhat reversed, with ∼1.5- to threefold lower expression in neurons for some of the enzymes (the outliers are the MCTs, which are required for the ANLS but are 40-fold lower in neurons).”

What the sources say

• Not checked yetcites Fig. 1

In the paper

“However, the use of pure lactate as an alternative fuel, rather than a redox-balanced mixture of lactate and pyruvate, abnormally elevates the low cytosolic NADH redox ratio in neurons (seen in vitro by Hung et al. [2011] and Mongeon et al. [2016] as well as in vivo by Díaz-García et al. [2017]); this decreases the rate of neuronal glycolysis in a way that would not represent the normal effect in”

What the sources say

• Not checked yetcites Hung et al., 2011 source
• Not checked yetcites Mongeon et al., 2016 source
• Not checked yetcites Díaz-García et al., 2017 source

In the paper

“however, recent data with high-pressure cryopreservation show much less astrocytic coverage of both capillaries and synapses than seen with aldehyde fixation, which shrinks the extracellular space (Korogod et al., 2015).”

What the sources say

• Not checked yetcites Korogod et al., 2015 source

In the paper

“Although one specific enzyme for up-regulation of glycolysis, the bifunctional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (isoform PFKFB3), is posttranslationally down-regulated in neurons and thus cannot participate in glycolytic stimulation (Herrero-Mendez et al., 2009; Bolaños, 2016), this rules out only one of many mechanisms that neurons can use to stimulate glycolysis.”

In the paper

“Moreover, detailed transport modeling shows that MCT2 is capable of ample lactate export from neurons at physiological concentrations (Simpson et al., 2007).”

What the sources say

• Not checked yetcites Simpson et al., 2007 source

In the paper

“Although they support the feasibility of the ANLS, these results do not demonstrate that astrocyte-to-neuron shuttling actually occurs during brain activation.”

In the paper

“Astrocytes can indeed produce lactate from glucose (Hertz et al., 1988; Magistretti et al., 1993), and this lactate production can be stimulated by glutamate and potassium, which become elevated during neuronal activity (Walz and Mukerji, 1988; Peng et al., 1994; Pellerin and Magistretti, 1996; Bittner et al., 2011).”

What the sources say

• Not checked yetcites Hertz et al., 1988 source
• Not checked yetcites Magistretti et al., 1993 source

In the paper

“Neurons express all of the enzymes needed for glucose metabolism (Fig. 1) and can metabolize glucose (Bak et al., 2009).”

What the sources say

• Not checked yetcites Bak et al., 2009 source

In the paper

“In vitro glycolytic behavior can change with choice of culture media (Sünwoldt et al., 2017) and astrocyte coculture (Mamczur et al., 2015), but gene expression data from acutely dissociated brain cells indicate that neurons are well equipped for glycolysis, with higher levels of mRNA expression than astrocytes for most glycolytic enzymes (Fig. 1, left).”

What the sources say

• Not checked yetcites Fig. 1

In the paper

“High-resolution autoradiographic analysis of [14C]–2-DG uptake in awake but unstimulated rats revealed roughly comparable label uptake in neurons and astrocytes (Nehlig et al., 2004); another in vivo labeling study using the fluorescent glucose analogue 2-NBDG showed stronger signals in neurons (Itoh et al., 2004).”

What the sources say

• Not checked yetcites Itoh et al., 2004 source

In the paper

“although again, the transporters are both equilibrative, and transcriptomics show comparable levels of MCT1 in both neurons and astrocytes (Fig. 1, left; the proteomics data on the right show an overall deficit of MCTs in neurons, but they are from cells in culture).”

What the sources say

• Not checked yetcites Fig. 1

In the paper

“The first study (Chuquet et al., 2010) used the fluorescent glucose analogue 6-NBDG; because it cannot be phosphorylated by hexokinase (given that the 6 position was already occupied by the fluorophore), this analogue’s accumulation may not correspond with the actual rate of glucose utilization, and it has been shown in some cases to correlate negatively with glucose utilization (DiNuzzo et al., 2”

What the sources say

• Not checked yetcites DiNuzzo et al., 2013 source

In the paper

“Astrocytes can indeed produce lactate from glucose (Hertz et al., 1988; Magistretti et al., 1993), and this lactate production can be stimulated by glutamate and potassium, which become elevated during neuronal activity (Walz and Mukerji, 1988; Peng et al., 1994; Pellerin and Magistretti, 1996; Bittner et al., 2011).”

What the sources say

• Not checked yetcites Walz and Mukerji, 1988
• Not checked yetcites Peng et al., 1994 source
• Not checked yetcites Pellerin and Magistretti, 1996

In the paper

“At the protein level, cultured neurons and astrocytes have substantial expression of the glycolytic enzymes (Fig. 1, right); here, the pattern is somewhat reversed, with ∼1.5- to threefold lower expression in neurons for some of the enzymes (the outliers are the MCTs, which are required for the ANLS but are 40-fold lower in neurons).”

What the sources say

• Not checked yetcites Fig. 1

In the paper

“although again, the transporters are both equilibrative, and transcriptomics show comparable levels of MCT1 in both neurons and astrocytes (Fig. 1, left; the proteomics data on the right show an overall deficit of MCTs in neurons, but they are from cells in culture).”

In the paper

“High-resolution autoradiographic analysis of [14C]–2-DG uptake in awake but unstimulated rats revealed roughly comparable label uptake in neurons and astrocytes (Nehlig et al., 2004); another in vivo labeling study using the fluorescent glucose analogue 2-NBDG showed stronger signals in neurons (Itoh et al., 2004).”

What the sources say

• Not checked yetcites Nehlig et al., 2004 source

In the paper

“Neurons express all of the enzymes needed for glucose metabolism (Fig. 1) and can metabolize glucose (Bak et al., 2009).”

What the sources say

• Not checked yetcites Fig. 1

In the paper

“The first study (Chuquet et al., 2010) used the fluorescent glucose analogue 6-NBDG; because it cannot be phosphorylated by hexokinase (given that the 6 position was already occupied by the fluorophore), this analogue’s accumulation may not correspond with the actual rate of glucose utilization, and it has been shown in some cases to correlate negatively with glucose utilization (DiNuzzo et al., 2”

What the sources say

• Not checked yetcites Chuquet et al., 2010 source

In the paper

“Using unstimulated cultured neurons, Bouzier-Sore et al. (2006) reported that resting neurons preferentially consume lactate over glucose.”

What the sources say

• Not checked yetcites Bouzier-Sore et al., 2006 source

In the paper

“however, both isoforms are rapidly equilibrative (as argued by Gandhi et al., 2009; Dienel, 2012; Hertz et al., 2014; Bak and Schousboe, 2017)”

What the sources say

• Not checked yetcites Gandhi et al., 2009 source
• Not checked yetcites Dienel, 2012 source
• Not checked yetcites Hertz et al., 2014 source

In the paper

“The first study (Chuquet et al., 2010) used the fluorescent glucose analogue 6-NBDG; because it cannot be phosphorylated by hexokinase (given that the 6 position was already occupied by the fluorophore), this analogue’s accumulation may not correspond with the actual rate of glucose utilization, and it has been shown in some cases to correlate negatively with glucose utilization (DiNuzzo et al., 2”

What the sources say

• Not checked yetcites Chuquet et al., 2010 source
• Not checked yetcites DiNuzzo et al., 2013 source

In the paper

“If an ANLS operates at rest, it could also explain why chronic disruption of MCT, LDH, or glycogenolysis in astrocytes can affect neuronal function (Suzuki et al., 2011; Zhang et al., 2016; Mazuel et al., 2017); these and similar results showing that MCT and lactate transport contribute to neuronal health and function provide evidence for some critical biological role for lactate uptake, but do”

What the sources say

• Not checked yetcites Suzuki et al., 2011 source
• Not checked yetcites Zhang et al., 2016 source
• Not checked yetcites Mazuel et al., 2017 source

In the paper

“These blockers instead lead to enhancement of the NADHCYT transients, suggesting that neurons normally export lactate when stimulated.”

In the paper

“A major limitation of all these studies is that the different analogues (which, except for 2-DG itself, are two- to sevenfold larger molecules than glucose) may have preferential transport through the different glucose transporter isoforms that are predominantly expressed in neurons or astrocytes (Vannucci et al., 1997).”

What the sources say

• Not checked yetcites Vannucci et al., 1997 source

In the paper

“With brief neuronal excitation in an acute hippocampal slice, NADHCYT rises rapidly and remains elevated for ∼2–3 min, reflecting a temporary imbalance favoring production of NADH over its recycling back to NAD+.”

What the sources say

• Not checked yetcites Díaz-García et al., 2017 source

In the paper

“In Drosophila melanogaster, glycolysis appears to be more essential in glial cells than it is in neurons; knockdown of glycolytic enzymes in neurons did not affect the viability or the general behavior of flies, whereas knockdown in glial cells produced noticeable phenotypic changes (Volkenhoff et al., 2015).”

What the sources say

• Not checked yetcites Volkenhoff et al., 2015 source

In the paper

“Using a different, phosphorylatable glucose analogue (2DG-IR) in nonanesthetized mice, better labeling was seen in neurons than astrocytes, particularly with whisker stimulation (Lundgaard et al., 2015).”

What the sources say

• Not checked yetcites Lundgaard et al., 2015 source

In the paper

“Pharmacologic blockade of MCT or of LDH abolishes the elevation of NADHCYT in response to exogenous lactate but not in response to stimulation, which rules out a role of lactate import in producing the transient increases in neuronal NADHCYT.”

What the sources say

• Not checked yetcites Díaz-García et al., 2017 source

In the paper

“Although ANLS thus does not seem to provide the primary source of neuronal energy during brain activation, a role for lactate shuttling from astrocytes to neurons at rest is possible.”

In the paper

“If an ANLS operates at rest, it could also explain why chronic disruption of MCT, LDH, or glycogenolysis in astrocytes can affect neuronal function (Suzuki et al., 2011; Zhang et al., 2016; Mazuel et al., 2017); these and similar results showing that MCT and lactate transport contribute to neuronal health and function provide evidence for some critical biological role for lactate uptake, but do”

What the sources say

• Not checked yetcites Mangia et al., 2011 source
• Not checked yetcites Hall et al., 2012 source
• Not checked yetcites Dienel, 2017 source

In the paper

“These blockers instead lead to enhancement of the NADHCYT transients, suggesting that neurons normally export lactate when stimulated.”

What the sources say

• Not checked yetcites Díaz-García et al., 2017 source

In the paper

“Consistent with most of the cultured cell studies, in resting brain or in quiescent brain slice astrocytes appear to be more glycolytic than neurons, with higher resting cytosolic NADH/NAD+ (NADHCYT) ratios (Mongeon et al., 2016) that predispose them to higher resting lactate/pyruvate ratios and higher resting lactate levels (Mächler et al., 2016).”

What the sources say

• Not checked yetcites Mongeon et al., 2016 source

In the paper

“Consistent with most of the cultured cell studies, in resting brain or in quiescent brain slice astrocytes appear to be more glycolytic than neurons, with higher resting cytosolic NADH/NAD+ (NADHCYT) ratios (Mongeon et al., 2016) that predispose them to higher resting lactate/pyruvate ratios and higher resting lactate levels (Mächler et al., 2016).”

What the sources say

• Not checked yetcites Mongeon et al., 2016 source
• Not checked yetcites Mächler et al., 2016 source

In the paper

“In summary, experiments on both cultured cells and intact tissue demonstrate that stimulated neurons augment their glucose, not lactate, utilization.”

In the paper

“If an ANLS operates at rest, it could also explain why chronic disruption of MCT, LDH, or glycogenolysis in astrocytes can affect neuronal function (Suzuki et al., 2011; Zhang et al., 2016; Mazuel et al., 2017); these and similar results showing that MCT and lactate transport contribute to neuronal health and function provide evidence for some critical biological role for lactate uptake, but do”

In the paper

“In Drosophila melanogaster, glycolysis appears to be more essential in glial cells than it is in neurons; knockdown of glycolytic enzymes in neurons did not affect the viability or the general behavior of flies, whereas knockdown in glial cells produced noticeable phenotypic changes (Volkenhoff et al., 2015).”

What the sources say

• Not checked yetcites Volkenhoff et al., 2015 source

In the paper

“Carbon tracing by magnetic resonance spectroscopy in vivo has great chemical specificity but cannot directly measure metabolism separately for neurons and glia, so the conclusions are dependent on the details of multicompartment modeling of metabolism.”

In the paper

“The difference in resting NADHCYT makes some baseline redox exchange likely between the two compartments (Cerdán et al., 2006); even with equal total (lactate + pyruvate) levels in the two cell types, astrocytic lactate could exchange for neuronal pyruvate, effectively allowing transfer of the glycolysis-derived NADH reducing equivalents from astrocytes to neurons.”

What the sources say

• Not checked yetcites Cerdán et al., 2006 source

In the paper

“The high level of glycolysis in photoreceptors is important as they perform substantial biosynthesis during their diurnal degradation and nocturnal regeneration of outer segments (Chinchore et al., 2017).”

What the sources say

• Not checked yetcites Chinchore et al., 2017 source

In the paper

“The inferred recruitment of direct neuronal glycolysis in response to stimulation in a relatively intact system is consistent with earlier carbon tracing studies on cultured neurons (Bak et al., 2009, 2012).”

What the sources say

• Not checked yetcites Bak et al., 2009 source
• Not checked yetcites Bak et al., 2012 source

In the paper

“However, this conclusion depends on the assumption that acetate is metabolized only in glia; a recent study of acetate metabolism in brain slices showed a substantial ability of neurons to metabolize acetate directly, which calls the compartment-specific modeling into question (Rowlands et al., 2017).”

What the sources say

• Not checked yetcites Rowlands et al., 2017 source

In the paper

“The NADHCYT transients decrease with inhibition of glycolysis but not of the MAS, indicating that increased neuronal glycolysis upon stimulation is the main cause of the NADHCYT transients.”

In the paper

“With brief neuronal excitation in an acute hippocampal slice, NADHCYT rises rapidly and remains elevated for ∼2–3 min, reflecting a temporary imbalance favoring production of NADH over its recycling back to NAD+.”

In the paper

“Pharmacologic blockade of MCT or of LDH abolishes the elevation of NADHCYT in response to exogenous lactate but not in response to stimulation, which rules out a role of lactate import in producing the transient increases in neuronal NADHCYT.”

In the paper

“The difference in resting NADHCYT makes some baseline redox exchange likely between the two compartments (Cerdán et al., 2006); even with equal total (lactate + pyruvate) levels in the two cell types, astrocytic lactate could exchange for neuronal pyruvate, effectively allowing transfer of the glycolysis-derived NADH reducing equivalents from astrocytes to neurons.”

In the paper

“Inhibition of MCT in vivo in the cortical neurons of awake mice also blocks the NADHCYT response to exogenous lactate but not to sensory stimulation.”

What the sources say

• Not checked yetcites Díaz-García et al., 2017 source

In the paper

“Other studies that considered mainly the compartmental origin of the NAD(P)H signal rather than the mechanism of production have made a strong case that both phases of the NAD(P)H signal are mostly from mitochondrial rather than cytosolic NADH.”

In the paper

“Either glucose or lactate can support transmission at high-frequency auditory presynaptic terminals (Lucas et al., 2018);”

What the sources say

• Not checked yetcites Lucas et al., 2018 source

In the paper

“The two most likely proximal signals are elevated [ADP] (the product of ATP hydrolysis) and elevated [Ca2+] (which accompanies most neuronal electrical signals by permeation through voltage- and neurotransmitter-activated channels).”

In the paper

“glial glycogen can supply energy to axons during aglycemia (Brown et al., 2003, 2012);”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Brown et al., 2003, 2012

In the paper

“Mitochondrial depolarization is important because in a resting mitochondrion, the ETC that pumps protons out of the matrix while consuming O2, and matrix NADH is nearly stalled by the buildup of the electrochemical proton gradient (ΔμH), which is itself a combination of the electrical (Δψ) and chemical (ΔpH) gradients.”

In the paper

“One candidate is the known effect of matrix Ca2+ in stimulating the matrix dehydrogenases including pyruvate dehydrogenase and the TCA dehydrogenases (McCormack et al., 1990).”

What the sources say

• Not checked yetcites McCormack et al., 1990 source

In the paper

“this study argued for lactate shuttling under limited conditions, but this conclusion is weak because MCT blockers that would also block mitochondrial pyruvate uptake were used (Halestrap and Denton, 1975; McKenna et al., 2001).”

What the sources say

• Not checked yetcites Halestrap and Denton, 1975
• Not checked yetcites McKenna et al., 2001 source

In the paper

“Many synaptic sites in brain have been shown to lack mitochondria (Chavan et al., 2015) and thus must depend on glycolysis”

In the paper

“mitochondria in dendritic shafts likely perform oxphos to supply needed energy.”

In the paper

“movement of mitochondria into the vicinity of synaptic sites has been demonstrated to affect both ATP levels and synaptic vesicle fusion in response to trains of stimulation (Sun et al., 2013).”

What the sources say

• Not checked yetcites Sun et al., 2013 source

In the paper

“Under ischemic conditions, lactate supplied exogenously or from astrocyte glycogenolysis is capable of providing metabolic support to neurons.”

In the paper

“in brain slices, [O2] shows a pronounced dip with stimulation, corresponding with increased O2 consumption (Hall et al., 2012; Liotta et al., 2012; Ivanov et al., 2014).”

What the sources say

• Not checked yetcites Hall et al., 2012 source
• Not checked yetcites Liotta et al., 2012 source
• Not checked yetcites Ivanov et al., 2014 source

In the paper

“Glycolysis alone can support presynaptic energy needs during very gentle stimulation (Lujan et al., 2016).”

What the sources say

• Not checked yetcites Lujan et al., 2016 source

In the paper

“Dendrites are sites of intense energy utilization (Hall et al., 2012),”

What the sources say

• Not checked yetcites Hall et al., 2012 source

In the paper

“In aglycemic conditions, glucose supplied to the gap junction–coupled network of oligodendrocytes was more effective than lactate in restoring axon function;”

What the sources say

• Not checked yetcites Meyer et al., 2018 source

In the paper

“However, it is hard to reconcile this with the clear finding by Shuttleworth et al. (2003) that the NAD(P)H overshoot in slices did not disappear with the prolonged elimination of extracellular Ca2+, although the mitochondrial Ca2+ transient did disappear.”

In the paper

“despite prior evidence in cultured neurons that mitochondria can localize to dendritic protrusions, particularly with stimulation (Li et al., 2004).”

What the sources say

• Not checked yetcites Li et al., 2004

In the paper

“Many synaptic sites in brain have been shown to lack mitochondria (Chavan et al., 2015)”

What the sources say

• Not checked yetcites Chavan et al., 2015 source

In the paper

“ADP and Ca2+ both have well-known effects on mitochondria and oxphos (Nicholls and Ferguson, 2002; Salway, 2004).”

What the sources say

• Not checked yetcites Nicholls and Ferguson, 2002
• Not checked yetcites Salway, 2004

In the paper

“In vivo uptake of 2-fluoro–2-DG into presynaptic terminals of rat brain assessed by postmortem isolation of synaptosomes (Patel et al., 2014) indicated substantial direct metabolism of glucose”

What the sources say

• Not checked yetcites Patel et al., 2014 source

In the paper

“Upon stimulation of neurons in a brain slice (Kann et al., 2003; Shuttleworth et al., 2003; Kasischke et al., 2004) or individual dissociated neurons (Duchen, 1992), the NAD(P)H signal has a stereotyped response: a rapid dip in fluorescence occurring within the first few seconds that yields in ∼10 s to a prolonged increase above baseline (overshoot) lasting for 2–3 min (Fig. 2 B).”

What the sources say

• Not checked yetcites Kann et al., 2003 source
• Not checked yetcites Shuttleworth et al., 2003 source
• Not checked yetcites Kasischke et al., 2004 source

In the paper

“In presynaptic terminals, both glycolysis and oxphos appear important for managing intense activity (Rangaraju et al., 2014; Sobieski et al., 2017).”

What the sources say

• Not checked yetcites Rangaraju et al., 2014 source
• Not checked yetcites Sobieski et al., 2017 source

In the paper

“Either glucose or lactate can be used as an energy source for white matter (Brown et al., 2001; Saab et al., 2016),”

What the sources say

• Not checked yetcites Brown et al., 2001 source
• Not checked yetcites Saab et al., 2016 source

In the paper

“In some postsynaptic structures, most notably the dendritic spines that receive most excitatory synaptic inputs in the mammalian brain, mitochondria were found to be absent in an exhaustive EM survey of a volume of neocortex (Kasthuri et al., 2015),”

What the sources say

• Not checked yetcites Kasthuri et al., 2015 source

In the paper

“however, in corpus callosum white matter, exogenous lactate could not support axon function in the absence of glucose (Meyer et al., 2018).”

What the sources say

• Not checked yetcites Meyer et al., 2018 source

In the paper

“consistent with an important role for glucose transporters and glycolysis in presynaptic terminals (Jang et al., 2016; Ashrafi et al., 2017; Ashrafi and Ryan, 2017).”

What the sources say

• Not checked yetcites Jang et al., 2016 source
• Not checked yetcites Ashrafi et al., 2017
• Not checked yetcites Ashrafi and Ryan, 2017

In the paper

“however, pharmacologic manipulation of MCTs and glucose transporters gave uncertain answers about how axonal support was provided (Meyer et al., 2018).”

What the sources say

• Not checked yetcites Meyer et al., 2018 source

In the paper

“but the relative importance of ADP and Ca2+ in initiating these signals is not agreed upon.”

In the paper

“The function of the MAS is antagonized by glutamate oxidation (LaNoue and Williamson, 1971; Du et al., 2013),”

What the sources say

• Not checked yetcites LaNoue and Williamson, 1971
• Not checked yetcites Du et al., 2013

In the paper

“Neuronal glycolytic regulation probably does not involve a key regulatory enzyme, PFKFB3 (Herrero-Mendez et al., 2009),”

What the sources say

• Not checked yetcites Herrero-Mendez et al., 2009 source

In the paper

“High NADHCYT limits pyruvate availability for oxidation by forcing pyruvate conversion to lactate.”

In the paper

“Uncoupling between glycolysis and oxphos involves the partitioning between pyruvate (the primary substrate for glucose-driven oxphos) and lactate.”

In the paper

“The clearest case for glial supply of energy to neurons is in ischemic situations, as shown best for white matter axons that can be supported by glial glycogen in the absence of an external supply of glucose (Brown et al., 2003).”

What the sources say

• Not checked yetcites Brown et al., 2003 source

In the paper

“however, at this time, there is more evidence for direct glucose utilization in presynaptic terminals than evidence for lactate uptake.”

In the paper

“There is also evidence that the glycolytic enzymes may be localized right where the neuron most requires acute resupply of ATP: at the plasma membrane and on the synaptic vesicles where major ion pumping is performed by transport ATPases (Ikemoto et al., 2003; Dhar-Chowdhury et al., 2007; Hinckelmann et al., 2016).”

What the sources say

• Not checked yetcites Ikemoto et al., 2003 source
• Not checked yetcites Dhar-Chowdhury et al., 2007 source
• Not checked yetcites Hinckelmann et al., 2016 source

In the paper

“The best direct evidence on this point is for neuronal cell bodies in both hippocampus and cerebral cortex,”

In the paper

“and there is ample evidence of glutamate oxidation by astrocytes (Hertz et al., 2007; Dienel, 2017).”

What the sources say

• Not checked yetcites Hertz et al., 2007 source
• Not checked yetcites Dienel, 2017 source

In the paper

“Certainly glycolysis alone is insufficient to power neuronal ion pumping (Hall et al., 2012),”

What the sources say

• Not checked yetcites Hall et al., 2012 source

In the paper

“but it may nevertheless play an important role in fast refueling.”

In the paper

“Another likely contributor to elevated cytosolic NADH redox in astrocytes is diminished shuttling of redox equivalents to mitochondria via the MAS.”

In the paper

“High NADHCYT can also limit the rate of glycolysis; this is commonly described as a deficiency in cytosolic NAD+ that is needed for glycolysis, but because NADHCYT rarely reaches as high as 0.1 (or even 0.01), this effect is probably better described as inhibition of the forward rate of the GAPDH reaction by the product NADH.”

In the paper

“This conversion of glucose to serine produces twice as much NADH as conversion of glucose to pyruvate (although flux through the first pathway may be smaller).”

In the paper

“For instance, astrocytes and not neurons express the phosphoglycerate dehydrogenase involved in serine biosynthesis (Ehmsen et al., 2013), which branches off of the main glycolytic pathway.”

What the sources say

• Not checked yetcites Ehmsen et al., 2013 source