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The Journal of Neuroscience, January 1, 1999, 19(1):34-39
An Increase in Lactate Output by Brain Tissue Serves to Meet the
Energy Needs of Glutamate-Activated Neurons
Avital
Schurr1,
James
J.
Miller2,
Ralphiel S.
Payne1, and
Benjamin M.
Rigor1
Brain Attack Research Laboratory, Departments of
1 Anesthesiology and 2 Pathology and Laboratory
Medicine, University of Louisville School of Medicine, Louisville,
Kentucky 40292
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ABSTRACT |
Aerobic energy metabolism uses glucose and oxygen to produce
all the energy needs of the brain. Several studies published over the
last 13 years challenged the assumption that the activated brain
increases its oxidative glucose metabolism to meet the increased energy
demands. Neuronal function in rat hippocampal slices supplied with 4 mM glucose could tolerate a 15 min activation by a 5 mM concentration of the excitatory neurotransmitter
glutamate (Glu), whereas slices supplied with 10 mM glucose
could tolerate a 15 min activation by 20 mM Glu.
However, in slices in which neuronal lactate use was inhibited by
the lactate transporter inhibitor a-cyano-4-hydroxycinnamate (4-CIN),
activation by Glu elicited a permanent loss of neuronal function, with
a twofold to threefold increase in tissue lactate content. Inhibition
of glycolysis with the glucose analog 2-deoxy-D-glucose
(2DG) during the period of exposure to Glu diminished normal neuronal
function in the majority of slices and significantly reduced the number
of slices that exhibited neuronal function after activation. However,
when lactate was added with 2DG, the majority of the slices were
neuronally functional after activation by Glu. NMDA, a
nontransportable Glu analog by the glial glutamate transporter, could
not induce a significant increase in slice lactate level when
administered in the presence of 4-CIN. It is suggested that the
heightened energy demands of activated neurons are met through
increased glial glycolytic flux. The lactate thus formed is a crucial
aerobic energy substrate that enables neurons to endure activation.
Key words:
hippocampal slices; energy metabolism; glutamate
excitation; lactate transport; glial glycolytic flux; neuronal
function
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INTRODUCTION |
Normally, the substrates of cerebral
energy metabolism are glucose and oxygen, and its products are ATP,
carbon dioxide, and water (Clarke and Sokoloff, 1994 ). Moreover, it has
been a long-held opinion that glucose is an obligatory energy substrate
in the brain. However, the assumption that the heightened energy needs of activated brain tissue are answered via oxidative metabolism of
glucose was challenged more than a decade ago (Fox and Raichle, 1986;
Fox et al., 1988), initiating an ongoing controversy (Hyder et al.,
1996; Malonek and Grinvald, 1996). Although many studies, using imaging
techniques such as functional magnetic resonance imaging (fMRI) and
blood oxygenation level-dependent fMRI, appear to support a
transient uncoupling between cerebral blood flow (CBF) and oxidative
metabolism after brain activation (Ogawa et al., 1992; Kim et al.,
1994; Ramsey et al., 1996; Kim and Ugurbil, 1997), other studies, using
the very same techniques, claim to observe a tight coupling between
CBF and oxidative metabolism (Buxton and Frank, 1997; Malonek et
al., 1997).
For years, elevated tissue lactate levels have been considered to
signal the existence of hypoxia and anaerobic energy metabolism (Friedmann and Barborka, 1941; Haljamae, 1987). Although substantial evidence has been accumulated to indicate that large amounts of lactate
can be produced in many tissues under fully aerobic conditions (Haljamae, 1987; Brooks, 1987), brain tissue has been presumed an exception. Thus, lactate production has been promoted as a major
detrimental factor in ischemic brain damage (Siesjö, 1981).
Many studies now suggest that the brain is not necessarily different
from other tissues, because it does produce lactate aerobically when
stimulated in both humans (Fox and Raichle, 1986; Fox et al., 1988;
Prichard et al., 1991; Raichle, 1991; Sappey-Marinier et al., 1992) and
animals (Fellows et al., 1993; Fray et al., 1996; Hyder et al.,
1996; Hu and Wilson, 1997). These results indicate that phasic changes
in neural activity are supported by glycolysis. Nevertheless, other
studies claim to demonstrate that oxidative metabolism of glucose meets
all the energy needs of the activated brain (Hyder et al., 1996;
Malonek and Grinvald, 1996).
In vitro research has shown that brain tissue produces
lactate under aerobic conditions and has demonstrated the ability of this tissue to respire when lactate is the energy source (McIlwain, 1953a,b, 1956). Our studies and those of others indicated that lactate
alone can support synaptic function in rat hippocampal slices (Schurr
et al., 1988; Stittsworth and Lanthorn, 1993; Izumi et al., 1994).
Lactate is a preferred substrate over glucose in sympathetic ganglia
(Larrabee, 1995, 1996). Cerebellar slices prepared from adult rats had
an increased ability to oxidize lactate to CO2 over slices
prepared from neonates (Bueno et al., 1994). Studies with primary
cultures of astrocytes (Pellerin and Magistretti, 1994; Magistretti et
al., 1995) demonstrated the ability of glutamate (Glu) to stimulate
glycolysis. These authors hypothesized that synaptically released Glu,
taken up by astrocytes, is the signal that couples neuronal activity to
glucose use. According to this hypothesis, astrocytic Glu uptake occurs
via Na+ cotransport. The ensuing outward
Na+ pumping activity is fueled by glycolysis. The
lactate thus released from astrocytes is taken up by neurons as an
aerobic energy substrate. This mechanism may explain the observed
increase in glucose use and lactate production, as short-lived as they
may be, without a concomitant increase in oxygen consumption after
brain stimulation. Obviously, oxygen consumption should quickly resume
for the oxidation of lactate by neurons. Unlike Glu, its analog NMDA is
not taken up by glia because it is not recognized by the Glu
transporter (Brew and Attwell, 1987; Rosenberg and Aizenmann, 1989;
Rosenberg et al., 1992; Irwin et al., 1994).
Recently, we reported that glial lactate produced during hypoxia is an
obligatory aerobic neuronal energy substrate after hypoxia (Schurr et
al., 1997a,b,c).
Here, we tested the hypothesis that activation by Glu induces an
increase in glial glycolytic flux to meet increased neuronal energy
demands. We also explored the role of lactate, produced during such
activation, in sustaining neuronal function after activation.
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MATERIALS AND METHODS |
Adult (200-350 gm) male Sprague Dawley rats were maintained and
used according to the guidelines of the Institutional Animal Care and
Use Committee. Hippocampal slices (400-µm-thick) were prepared using
a McIlwain tissue chopper. Slices were placed in a dual
incubation-recording chamber (12-15 slices per compartment) (Schurr
et al., 1985) where the temperature was maintained at 34 ± 0.3°C, supplied with a humidified gas mixture (95%
O2-5% CO2), and perfused with
artificial CSF (aCSF) (60 ml/hr) of the following composition
(in mM): NaCl 124, KCl 5, NaH2PO4
3, CaCl2 2.5, MgSO4 2, NaHCO3 23, and D-glucose 10 or 4, as indicated. The pH of the aCSF was
7.3-7.4. Where indicated, D-glucose was replaced with 10 mM 2-deoxy-D-glucose (2DG). Glu, NMDA, lactate (sodium salt), or  -cyano-4-hydroxycinnamate (4-CIN) was added via
the aCSF. All chemicals were obtained from Sigma (St. Louis, MO).
Extracellular recordings of evoked population spikes (neuronal
function) were made using borosilicate micropipettes (2-5 M ). Bipolar stimulating electrodes were placed in the Schaffer collaterals (orthodromic stimulation), and stimulus pulses of 0.1 msec in duration
and amplitude of 8-10 V were applied once per minute. A waveform
analysis program was used to determine the amplitude of the evoked
response. Any slice that exhibited a population spike with an amplitude
of  3 mV was considered to be neuronally functional (Schurr et al.,
1997a,b,c).
Lactate and glucose were measured using the enzymatic kits of Sigma, as
described elsewhere (Schurr et al., 1997a,b,c).
Each data point in the experiments described in this study was repeated
at least three times unless indicated otherwise. Values are mean ± SD. Statistical analyses for significant differences were performed
using the paired t test for biochemical data and the
 2 test for electrophysiological data.
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RESULTS |
Because glucose is the main fuel of brain tissue during both rest
and activation, we performed all the Glu experiments using two
different glucose concentrations, 4 and 10 mM, in the aCSF that perfused the slices. This was done with the assumption that the
higher the glucose concentration during activation, the higher the
level of lactate produced by glia, and thus, the higher the concentration of Glu that slices would tolerate. Table
1 (treatments 1, 2, 7, 8) shows the
electrophysiological outcome, and Figure 1 illustrates the biochemical outcome of
exposing hippocampal slices to either 5 or 20 mM Glu in the
absence or presence of the lactate transporter inhibitor 4-CIN (0.25 or
0.5 mM, respectively). This inhibitor was shown to inhibit
neuronal lactate uptake in hippocampal slices (Schurr et al., 1997b)
but not glial export of lactate (Volk et al., 1997). After 30 min of
Glu washout, the majority of control slices exhibited normal neuronal
function (population spike amplitude, 3 mV). Only 3 of 77 slices that were exposed to Glu in the presence of 4-CIN were neuronally functional after Glu washout (Table 1, treatments 2, 8). Biochemically, Glu was
found to induce the accumulation of lactate in 4-CIN-treated hippocampal slices. In contrast, such accumulation was not observed in
control slices (Fig. 1A,B). In both
sets of slices, tissue glucose levels had not changed significantly
during the exposure to Glu (results not shown). NMDA (20 µM) had a similar effect to that of Glu on neuronal
function of 4 mM glucose-perfused hippocampal slices, i.e.,
an observable decline in population spike amplitude during 15 min of
NMDA perfusion, with the majority of slices exhibiting preservation of
neuronal function 30 min after NMDA washout (Table 1, treatment 5).
Higher concentrations of NMDA (50-100 µM) diminished neuronal function in all slices, even after its washout, whereas a
lower NMDA concentration (10 µM) was innocuous (results
not shown). None of the slices that were exposed to 20 µM
NMDA with 0.25 mM 4-CIN exhibited neuronal function 30 min
after NMDA washout (Table 1, treatment 6). However, in contrast to the
effect of Glu, when slices were perfused with NMDA (20 µM) in the presence of 4-CIN (0.25 mM), slice
lactate level did not increase significantly (Fig.
2).
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Table 1.
The ratios of rat hippocampal slices incubated in either 4 or 10 mM glucose-aCSF that were neuronally functional
(showing an orthodromically evoked CA1 population spike of an amplitude
3 mV) after 15 min perfusion with Glu (5 or 20 mM) or
NMDA (20 µM) and 30 min of its washout
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Figure 1.
Tissue content of lactate before
(Baseline) and during (shaded area)
exposure to Glu and during Glu washout (Washout) in
control (open symbols) and 4-CIN-treated
(filled symbols) rat hippocampal slices perfused
with either 4 (A) or 10 mM
(B) glucose-aCSF. *p < 0.03; **p = 0.01; ***p < 0.004, significantly different from control.
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Figure 2.
Tissue content of lactate before
(Baseline) and during (shaded area)
exposure to NMDA and during NMDA washout (Washout) in
control (open symbols) and 4-CIN-treated
(filled symbols) rat hippocampal slices perfused
with 4 mM glucose-aCSF. Asterisks indicate
that assay was done in duplicates only.
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When 4 mM glucose was replaced with its nonmetabolizable
analog 2DG during the period of 5 mM Glu perfusion (Table
1, treatment 3), <50% of the slices exhibited neuronal function after
30 min of washout. When the same experiment was done with slices
perfused with 10 mM glucose and 20 mM Glu
(Table 1, treatment 9), none of the slices were neuronally functional
after 30 min of Glu washout. However, when lactate was supplemented
with 2DG (Table 1, treatments 4, 10), the majority of the slices were
neuronally functional at the end of the Glu washout period.
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DISCUSSION |
We suggest that the higher level of lactate found in slices
perfused with 10 mM glucose compared with those perfused
with 4 mM glucose (Fig. 1, baseline) is
responsible for the ability of the former to tolerate a higher
concentration of Glu. This conclusion stems from the fact that 20 mM Glu, although having no effect on slices maintained on
10 mM glucose, completely diminished the neuronal function
of slices maintained on 4 mM glucose (results not shown).
Although the concentrations of Glu used in this study (5 and 20 mM) could be considered excitotoxic rather than
stimulating, slices incubated with high enough glucose levels (4 and 10 mM, respectively) showed no ill effects after Glu washout.
Moreover, excitotoxicity could very well be considered a case of
overactivation. After all, any interference with normal Glu uptake by
glia through a disturbance in energy metabolism (hypoxia, inhibition of
glycolysis, etc.) enhances the excitotoxic effects of Glu (Novelli et
al., 1988; Henneberry, 1989; Schurr et al., 1989). We interpreted the results shown in Figure 1 to indicate that under control conditions any
lactate formed during exposure to Glu was immediately consumed by
neurons as an aerobic energy substrate. The majority of lactate formation is most probably extraneuronal, i.e., glial. Two separate results support this conclusion. First, lactate transport into neurons
is inhibited by 4-CIN (Schurr et al., 1997b), an inhibitor that was
found to be ineffective in inhibiting glial export of lactate (Volk et
al., 1997). If the majority of the lactate produced during exposure to
Glu was neuronal in origin, 4-CIN would be without an effect. By
inhibiting lactate transport into neurons, 4-CIN prevented its use and,
eventually, the preservation of neuronal function after Glu washout.
This is despite the ample supplies of glucose throughout the duration
of the experiment. A 60 min perfusion of slices with 4-CIN (0.25 or 0.5 mM) without Glu did not change the levels of either glucose
or lactate compared with untreated slices and had no effect on neuronal
function, indicating that any increase in lactate level as shown in
Figure 1 was induced by Glu rather than by the lactate transporter
inhibitor. Nevertheless, Izumi and colleagues (1997) demonstrated that
when glucose supplies are very limited, synaptic function is sustained
by monocarboxylates, because inhibition of monocarboxylate transport
with 4-CIN depressed neuronal EPSP of hippocampal slices and produced
significant neuronal damage.
The second result in support of the postulate that glia are the main
source of glycolytic lactate is the outcome of the experiments with
NMDA (Fig. 2; Table 1, treatments 5, 6). NMDA, a Glu analog that is not
recognized by the glial Glu transporter (Brew and Attwell, 1987;
Rosenberg and Aizenmann, 1989; Rosenberg et al., 1992; Irwin et al.,
1994), could not induce a significant increase in slice lactate level
in the presence of 4-CIN. The fact that slices treated with 20 µM NMDA in the presence of 0.25 mM 4-CIN could not preserve neuronal function after washout of the excitotoxin highlights the importance of the basal level of lactate (15-20 nmol/slice) in protecting neurons from the damaging effects of activation. When the neuronal uptake of this basal lactate was blocked
with 4-CIN, neuronal function was not protected from the toxic effect
of NMDA. Moreover, this basal level of lactate is apparently
insufficient for protection of neuronal function against the toxic
effect of 50 or 100 µM NMDA. The fact that NMDA did not
induce a significant increase in lactate production also argues against
the possibility that this excitotoxin evokes the release of Glu,
because such release would result in lactate production.
If glycolytic activity is of paramount importance during activation of
brain tissue by Glu, one could speculate that blockade of glycolysis
would weaken the ability of hippocampal slices to maintain neuronal
function during 15 min exposure to Glu. Moreover, one could expect a
diminishment in neuronal function after blockade of glycolysis in the
presence of Glu, even after washout of the excitotoxin. Precisely this
occurred when glucose was replaced with 2DG, a nonmetabolizable glucose
analog and thus a glycolytic inhibitor, during the period of activation
by Glu (Table 1, treatments 3, 9). Lactate supplementation with 2DG
(Table 1, treatments 4, 10) preserved neuronal function in the majority
of the slices at the end of the Glu washout period. This outcome
clearly indicates that lactate plays a crucial role in assuring the
preservation of neuronal viability during periods of brain tissue activation.
Based on the results of this investigation, we offer the following
scenario (Fig. 3) for brain energy
metabolism during a resting state and during activation (exposure to
Glu) using the dual compartment model of Pellerin and Magistretti
(1994). Under resting conditions, most of the glucose taken up by the
brain from the blood supply is metabolized oxidatively in both the
glial and neuronal compartments. Most of the basal lactate produced in
glia is transported into neurons where it directly enters the neuronal
TCA. After activation (exposure to Glu), an immediate glial Glu uptake
is initiated, accompanied by Na+ transport (Pellerin
and Magistretti, 1994, 1997; Magistretti et al., 1995). The need to
pump out this extra Na+ brings about a dramatic
increase in glial Na-K-ATPase activity and thus an equally dramatic
increase in glucose consumption, most of which is glycolytic, as was
evidenced by the large increase in lactate production in the presence
of 4-CIN. A plausible explanation for the observed increase in this
nonoxidative lactate production could be the existence of a separate
glycolytic pathway, the sole purpose of which is to provide the glial
Na-K-ATPase system with its own ATP supply (Lipton and Robacker, 1983).
Because such a pathway does not require oxygen for its activity, no
increase in oxygen consumption would be observed after its activation. The large amount of glial lactate produced under conditions of activation (Fig. 1) is transported out of glia by a specific glial lactate transporter (Bröer et al., 1997; Volk et al., 1997) and into neurons via a specific neuronal transporter. In neurons, lactate
becomes the main aerobic energy substrate because of the concomitant increase in neuronal lactate/glucose ratio (Larrabee, 1995,
1996). The increase in neuronal lactate use is accompanied by a
decrease in neuronal glucose use or a reduced neuronal glycolytic flux
(Larrabee, 1995, 1996). This scenario would explain the observation made by many investigators that the stimulation of brain tissue increases glucose uptake and consumption without a concomitant increase
in O2 consumption (Fox and Raichle, 1986; Prichard et al.,
1991; Raichle, 1991; Sappey-Marinier et al., 1992; Fellows et al.,
1993; Magistretti et al., 1995), an increase that could be blunted by
the decrease in neuronal glucose consumption as neurons shift into
lactate use. Moreover, in vivo studies of energy metabolism
of activated brain tissue (Fox and Raichle, 1986; Prichard et al.,
1991; Raichle, 1991; Sappey-Marinier et al., 1992; Ogawa et al., 1992;
Fellows et al., 1993; Kim et al., 1994; Magistretti et al., 1995; Hyder
et al., 1996; Malonek and Grinvald, 1996; Ramsey et al., 1996; Kim and
Ugurbil, 1997) cannot separate between the glial and the neuronal
compartments and thus measure the sum of changes of both oxidative and
nonoxidative glucose metabolism in both compartments. It is possible
that a significant elevation in glial glucose consumption via increased
glycolytic flux is masked by a significant decrease in neuronal
oxidative use of glucose given that neuronal TCA flux during activation
is supported almost entirely by consumption of glial lactate. After
activation, this scenario thus envisions a total increase in glucose
consumption, primarily glial and nonoxidative, and a decrease in
neuronal oxidative glucose consumption, which is being replaced by an
oxidative use of glial lactate. In other words, in each compartment,
the normal resting stoichiometry of
O2/glucose could change dramatically after
activation. The glial compartment would exhibit a decrease in
O2/glucose because of an increase in glycolytic
flux, whereas the neuronal compartment would exhibit an increase in
O2/glucose because of a reduction in glucose
consumption and a significant increase in oxidative use of glial
lactate. Consequently, the measured sum of the
O2/glucose stoichiometry of both compartments, as is
the case in vivo, could remain close to the normal value. Recently, Sibson et al. (1998) determined that the stoichiometry between oxidative glucose metabolism and glutamatergic neuronal activity in the cortex in vivo is close to 1:1, implying
that the majority of the energy produced during activation supports glutamatergic neuronal function. Moreover, these authors envisioned that during neuronal Glu release and its glial uptake astrocytic glycolysis is the main glucose consumer, and neuronal lactate use is
the main oxygen consumer.
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Figure 3.
Schematic diagram of the two main pathways of
energy metabolism, glycolysis, and oxidative phosphorylation in two
brain tissue compartments, neuronal and glial, during resting state
(left) and during a state of activation
(right). For more details, see Results.
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In summary, our results strongly support the hypothesis that the energy
needs of activated brain tissue are met through glial nonoxidative
glucose consumption, which significantly increases lactate production.
This extra lactate becomes a major neuronal oxidative energy substrate
that significantly reduces the neuronal glucose consumption.
These findings could have broad implications for the understanding
of the coupling between brain stimulation and energy metabolism and for
several major brain disorders.
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FOOTNOTES |
Received March 17, 1998; revised Oct. 13, 1998; accepted Oct. 16, 1998.
We thank C. Maldonado and H. L. Neibergs for helpful discussions
and P. Bensinger for excellent editorial expertise.
Correspondence should be addressed to Avital Schurr, Brain Attack
Research Laboratory, Department of Anesthesiology, University of
Louisville, School of Medicine, Louisville, KY 40292.
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Abstract
Introduction
Compound via MeSH
