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The Journal of Neuroscience, September 15, 2000, 20(18):6804-6810
Astrocytic Glycogen Influences Axon Function and Survival during Glucose Deprivation in Central White Matter
Regina Wender1, 2, Angus M. Brown1, Robert Fern1, Raymond A. Swanson3, Kevin Farrell3, and Bruce R. Ransom1, 2 Departments of 1 Neurology and 2 Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington 98195, and 3 Department of Neurology, University of California, San Francisco, and Veterans Affairs Medical Center, San Francisco, California 94121
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
We tested the hypothesis that astrocytic glycogen sustains axon function during and enhances axon survival after 60 min of glucose deprivation. Axon function in the rat optic nerve (RON), a CNS white matter tract, was monitored by measuring the area of the stimulus-evoked compound action potential (CAP). Switching to glucose-free artificial CSF (aCSF) had no effect on the CAP area for ~30 min, after which the CAP rapidly failed. Exposure to glucose-free aCSF for 60 min caused irreversible injury, which was measured as incomplete recovery of the CAP. Glycogen content of the RON fell to a low stable level 30 min after glucose withdrawal, compatible with rapid use in the absence of glucose. An increase of glycogen content induced by high-glucose pretreatment increased the latency to CAP failure and improved CAP recovery. Conversely, a decrease of glycogen content induced by norepinephrine pretreatment decreased the latency to CAP failure and reduced CAP recovery. To determine whether lactate represented the fuel derived from glycogen and shuttled to axons, we used the lactate transport blockers quercetin,
-cyano-4-hydroxycinnamic acid (4-CIN), and p-chloromercuribenzene sulfonic acid (pCMBS). All transport blockers, when applied during glucose withdrawal, decreased latency to CAP failure and decreased CAP recovery. The inhibitors 4-CIN and pCMBS, but not quercetin, blocked lactate uptake by axons. These results indicated that, in the absence of glucose, astrocytic glycogen was broken down to lactate, which was transferred to axons for fuel.
Key words: astrocytes;
INTRODUCTION
The function of brain glycogen is not well understood. Glycogen turns over rapidly in the brain, however, and turnover is enhanced when adjacent neural activity is increased (Orkand et al., 1973
; Pentreath and Kai-Kai, 1982
Given all of the above, it is natural to wonder whether glycogen can enhance the survival and function of brain tissue in the absence of glucose. Surprisingly, only a single study, done on cultured cells, has tested this question. Neurons grown in astrocyte-rich cultures are injured less severely by glucose withdrawal than are neurons in astrocyte-poor cultures (Swanson and Choi, 1993
We have studied the role of astrocytic glycogen in an in vitro preparation of CNS white matter, the isolated rat optic nerve (RON). An advantage of this preparation is that function can be monitored continuously. Optic nerve function persists for ~30 min in the absence of glucose (Ransom and Fern, 1997
MATERIALS AND METHODS
Preparation. Long-Evans rats were anesthetized deeply with CO2 and then decapitated. The optic nerves were exposed, gently freed from their dural sheaths, and placed in an interface perfusion chamber (Medical Systems, Greenvale, NY) (see also Stys et al., 1990
, 26 HCO3
Data were acquired online (Digidata 1200A, Axon Instruments, Foster City, CA) with proprietary software (Axotape, Axon Instruments). CAP area was calculated with Clampfit (Axon Instruments).
Curve fitting. To standardize data interpretation, we used a mathematical approach to analyze CAP area. This approach is based on the Boltzmann equation because, as illustrated in Figure 1C, plotting CAP area against time during glucose removal (our standard insult) resulted in a trace that can be resolved into two sigmoidal curves, each of which can be fit by a Boltzmann function, one with a negative (falling) slope and the other with a positive (rising) slope. Our goal was to use the Boltzmann equation to define precisely the point of CAP decline and the maximum amount of CAP recovery (see Fig. 1C). The Boltzmann relationship is described by:
where y is the area under the CAP curve, max is the maximum value of the described sigmoidal (designated max1 for the first sigmoidal, of negative slope, and max2 for the second sigmoidal, of positive slope), V is the time at which the CAP area is 50% of max, t is the time, and k is the slope at point V. It is important to note that max1 and max2 are not necessarily the highest CAP area values from the baseline and recovery periods, respectively, but rather are the maximum values of the described sigmoidals. The minimum value for any data set is defined by the function as zero. The solid line superimposed on the data set shown in Figure 1C was generated by fitting the Boltzmann equation to the data. The break in the curve, indicated by the downward-pointing vertical arrow, identifies the point at which the equation has identified the zero point. The equation is applied separately to the second curve (of positive slope). In this case the maximum point as determined by curve fitting is represented by max2, which describes CAP recovery. When this equation was applied to every data set, it was possible to calculate the latency of onset of CAP decline, defined as t = 0.95·max1, and CAP recovery, defined as (max2/max1) × 100%.
Transmission electron microscopy. Adult male Long-Evans rats were anesthetized deeply with ketamine/xylazine (40/2.5 mg/kg of body weight, i.p.) and perfused transcardially, first with a PBS solution and then with a fixative solution containing 2% paraformaldehyde and 2% glutaraldehyde in 0.14 M phosphate buffer, pH 7.4. Optic nerves were freed carefully and placed in fresh fixative overnight at 4°C. Then the tissue was rinsed several times in 0.14 M phosphate buffer, post-fixed in 1% OsO4 and 1.5% potassium ferrocyanide in 0.14 M phosphate buffer for 3 hr at 4°C, and rinsed several times in phosphate buffer. The nerves were dehydrated in a graded ethanol series and embedded in Epon. Silver-gray sections were cut with a Reichardt Ultracut E and contrasted with uranyl acetate and lead citrate.
Glycogen and protein assays. Nerves were placed immediately in 3 ml of ice-cold 85% ethanol/15% 30 mM HCl. This instantly stops glycogen metabolism. The tissue (in solution) was stored at
20°C until assays were performed. Assays were performed as previously described (Swanson and Choi, 1993
Data analysis. Data are presented as means and SEM. Significance was determined by ANOVA with Tukey's post-test, where p < 0.05 was taken to indicate statistical significance.
RESULTS
The effects of glucose deprivation on CAP area in adult RONs are shown in Figure 1. CAPs were evoked every 30 sec. During a 60 min period of glucose withdrawal the CAP was maintained, on average, for 28.8 ± 2.1 min (n = 15) before it began to fail (Fig. 1A). It fell rapidly from that point to zero. The CAP recovered to an average of 45.3 ± 3.7% (n = 15) of the control CAP after a 60 min recovery period in normal aCSF (i.e., containing 10 mM glucose), indicating that irreversible injury had occurred. This agreed with previously published results (Ransom and Fern, 1997
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Figure 1. Effects of glucose withdrawal for 60 min on the rat optic nerve CAP area. A, A 60 min period of glucose withdrawal caused failure of the CAP after ~30 min and resulted in incomplete CAP recovery. Each symbol represents average CAP area (evoked every 30 sec; n = 15). B, Representative CAPs recorded from one of the nerves averaged in A. The recordings were taken at the time points indicated (a-c). Calibration: 0.5 mV, 1 msec. C, Representative trace from an individual nerve included in A to illustrate the curve-fitting protocol that was used to quantify latency and recovery.
Ultrastructural identification of astrocytic glycogen in the RON
Electron microscopy studies performed on perfusion-fixed RONs (Fig. 2) showed granules of glycogen located within most astrocytes. No glycogen was seen in axons or oligodendrocytes. No attempts were made to quantify the glycogen seen in this manner. These results agreed with previous studies on other neural areas (Cataldo and Broadwell, 1986
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Figure 2. Ultrastructural evidence of glycogen deposition in astrocytes in adult rat optic nerve. Electron micrograph shows accumulations of glycogen granules (gly), which are ~20-25 nm in diameter, within processes of astrocytes (As) at the glia limitans (GL). Glycogen granules were not seen in axons nor in oligodendrocytes. Scale bar, 0.25 µm.
Glycogen content of RON
The levels of glycogen in RONs under different conditions were determined by biochemical assay (Fig. 3). Glycogen content declined in vitro after the removal of nerves from the animal. In one set of experiments, for example, glycogen content fell from 10.10 ± 0.72 pmol of glycogen/µg of protein (n = 6) immediately after dissection (i.e., the nerves were never placed in the tissue chamber) to 4.85 ± 0.31 pmol of glycogen/µg of protein (n = 6; p < 0.001) in companion nerves that were perfused with control aCSF for 60 min (see Fig. 3B, first bar). Nonetheless, glycogen content of RONs was quite stable after 60 min of incubation in control aCSF containing 10 mM glucose (Fig. 3A, compare the first and last bars). It should be noted that the absolute values of glycogen in nerves under control conditions (60 min incubation in aCSF containing 10 mM glucose) were variable between assay sets (e.g., Fig. 3, compare the first bar in A with the first bar in B), but results within each set of assays were internally consistent.
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Figure 3. Glycogen content of rat optic nerves after glucose deprivation and pharmacological manipulation. A, In the absence of glucose, glycogen content declined over time and reached a low stable level at 30 min. The cross-hatched bar at 120 min shows the glycogen content of nerves that were allowed to recover for 60 min in control aCSF after the 60 min period of glucose withdrawal. The clear bar at 120 min represents the glycogen content of nerves that were perfused with control aCSF for the entire 120 min test period, with no exposure to glucose-free aCSF. Time (min) refers to the time elapsed from the beginning of glucose-free perfusion. All of the nerves in this experiment were incubated first in control aCSF for 60 min; n = 6 for all conditions except 60 min (n = 4). Error bars indicate SEM. *p < 0.05 and ***p < 0.001 as compared with 0 min. B, Incubation of nerves with 25 mM glucose increased glycogen content, and incubation with NE caused glycogen to decline. Glycogen content in nerves pretreated with 25 mM fructose was not significantly different from control. All of the nerves were incubated for 60 min in the indicated substrate beginning immediately after their removal from the animal; n = 6 for each group except NE (n = 7). Error bars indicate SEM. n.s., Not significant; **p < 0.01 and ***p < 0.001 as compared with control.
In one set of experiments we investigated the effects of glucose removal on glycogen content. All nerves were given an initial 60 min incubation period in control aCSF containing 10 mM glucose. The glycogen content fell rapidly with glucose removal (Fig. 3A). From an initial value of 10.70 ± 0.45 pmol of glycogen/µg of protein (t = 0 min; n = 6), glycogen fell to 8.37 ± 0.35 pmol of glycogen/µg of protein after 15 min of glucose deprivation (n = 6; p < 0.05 vs 0 min group) and then to a low stable level after 30 min (2.69 ± 0.30 pmol of glycogen/µg of protein; n = 6). One group of nerves was allowed to recover for 60 min in control aCSF after the 60 min period of glucose withdrawal (cross-hatched bar at 120 min in Fig. 3A; 3.06 ± 0.33 pmol of glycogen/µg of protein; n = 6). Glycogen content in this group was not significantly different from glycogen content in nerves that were not given a recovery period (p > 0.05 compared with nerves collected at 30, 45, and 60 min). The glycogen content of nerves that were simply perfused with control aCSF for the entire 120 min test period, with no period of glucose deprivation, was not significantly different from the control nerve glycogen content (11.1 ± 0.89 pmol of glycogen/µg of protein; n = 6; p > 0.05 compared with control and p < 0.001 compared with cross-hatched bar).
As a crucial step to testing the effects of glycogen on RON function, we determined whether RON glycogen content could be modulated. These results are shown in Figure 3B. For this set of nerves the control population incubated for 60 min in normal aCSF contained 4.85 ± 0.31 pmol of glycogen/µg of protein (n = 6). In other preparations exposure to high glucose concentration increases glycogen content (Prasannan and Subrahmanyam, 1966
Glycogen content and axon function
To determine whether RON glycogen content affected axon function during glucose withdrawal, we assessed the CAP during glucose withdrawal in nerves for which the glycogen was increased or decreased (Fig. 4). Nerves with increased glycogen (i.e., preincubated with 25 mM glucose), as compared with control nerves, showed increased latency to CAP area decline during glucose deprivation [41.5 ± 4.9 min (n = 6) vs control at 28.9 ± 2.1 min (n = 15); p < 0.05]. The CAP never fell to zero during aglycemia in the high-glycogen nerves (Fig. 4A). Nerves with decreased glycogen (i.e., preincubated with 1 mM norepinephrine) all had latencies to CAP decline of <28 min, the average latency to CAP decline in control nerves, but this trend did not reach statistical significance (23.2 ± 1.1 min; n = 9; p > 0.05 vs control). The magnitude of post-aglycemia CAP recovery for nerves with variable glycogen content is illustrated in Figure 4B. CAP recovery after glucose withdrawal was significantly greater in high-glycogen nerves (85.8 ± 7.2%; n = 6; p < 0.001) and significantly less in low-glycogen nerves (20.2 ± 3.3%; n = 9; p < 0.01) as compared with control tissue (45.3 ± 3.7%; n = 15).
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Figure 4. Effect of nerve glycogen content on axon function during, and recovery from, a 60 min period of glucose deprivation. A, Increase of glycogen by pretreatment of optic nerves with 25 mM glucose (n = 6) delayed the onset of CAP area decline during 60 min of glucose deprivation as compared with control (n = 15). Under these conditions the magnitude of CAP recovery was greater. Decrease of glycogen by pretreatment with 1 mM norepinephrine decreased the extent of CAP recovery (n = 9). B, Percentage of CAP recovery 60 min after exposure to glucose-free aCSF for the nerves represented in A. Control nerves showed recovery of CAP area to 45.3 ± 3.7%. Pretreatment of nerves with 25 mM glucose increased CAP recovery, and incubation with 1 mM norepinephrine had the opposite effect. **p < 0.01 and ***p < 0.001 as compared with 10 mM glucose group.
To confirm that the results observed with 25 mM glucose were attributable to the presence of increased glycogen stores and were not merely a consequence of "loading" of the extracellular space with elevated glucose, we performed a series of experiments with 25 mM fructose. Fructose, like glucose, sustains the CAP, but it does not induce glycogen synthesis (Wiesinger et al., 1997
We determined whether glycogen content would affect the latency of CAP failure or the degree of CAP recovery after an anoxic insult as opposed to an aglycemic insult. Nerves with increased or decreased glycogen content were subjected to 60 min periods of anoxia. RON glycogen content had no apparent effect on the time course of CAP failure or on the degree of CAP recovery from anoxia (data not shown).
Blockade of lactate transport and axon function during glucose withdrawal
Nerves in control aCSF containing 10 mM glucose maintained robust CAPs for several hours (Fig. 5A), in agreement with Stys et al. (1991)
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Figure 5. Lactate supported RON function in the absence of glucose and in the presence of the lactate transport blocker quercetin. A, Nerves continually perfused with control aCSF showed no decline in average CAP area over 120 min (n = 6). Lactate could substitute for glucose in maintaining the CAP for the 60 min period shown by the solid horizontal line (n = 6). B, Effect of quercetin (50 µM) on RONs subjected to 60 min of glucose withdrawal. Quercetin had no effect on the average CAP of nerves perfused with 10 mM glucose (n = 6). Quercetin also had no effect on the CAP of nerves exposed to 20 mM lactate during glucose withdrawal (n = 6). When quercetin was applied during 0 mM glucose exposure, however, there was a decline in CAP area and reduced recovery (n = 7).
Because lactate served as an effective energy source for axon function and appears in the extracellular space with glycogen breakdown (Dringen et al., 1993
Two other lactate transport inhibitors,
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Figure 6. Effect of the lactate transport inhibitors 4-CIN and pCMBS on RONs exposed to 0 or 10 mM glucose or 20 mM lactate for 60 min. A,
When pCMBS, a specific blocker of the monocarboxylate transporter isoform MCT1 (Halestrap and Price, 1999
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Figure 7. Summary of CAP recoveries after aglycemia with inhibition of lactate transport, with and without lactate supplementation. The four bars on the left represent nerves that were subjected to a 60 min period of glucose withdrawal, i.e., no exogenous substrate was provided. A second set of nerves, represented by the four bars on the right, was exposed to the indicated lactate transport blockers during aglycemia but in the presence of 20 mM lactate. Each bar represents a minimum of six experiments. Error bars indicate SEM. **p < 0.01 and ***p < 0.001 as compared with no blocker in 0 mM glucose group; +++p < 0.001. n.s., Not significant as compared with no blocker in 20 mM lactate group.
DISCUSSION
Our results support the hypothesis that, during glucose deprivation in white matter, astrocytes supply energy substrate to axons in the form of lactate derived from glycogen. This is, to our knowledge, the first demonstration of the importance of astrocytic glycogen for axon function and survival during glucose withdrawal. Our conclusions are based on the following observations: (1) the RON contained glycogen localized exclusively in astrocytes; (2) in the absence of glucose, RON axons remained functional for 30 min and then failed with a time course that mirrored glycogen loss; (3) RON function during and after 60 min of glucose removal was enhanced by increasing glycogen content and decreased by decreasing glycogen content; (4) lactate supported RON function in the absence of glucose; and (5) blockade of transmembrane lactate transport decreased RON function in the absence of glucose.
The persistence of the CAP for 30 min without glucose suggested the presence of an intrinsic energy reserve. Brain glycogen, localized almost exclusively in astrocytes (see Fig. 2), is a prime candidate to fill this role (Cataldo and Broadwell, 1986
We feel confident that the electron-dense particles located in glial end-feet (see Fig. 2) are glycogen, on the basis of two observations. First, the only other structure with which these might be confused is free ribosomes, which at 10-15 nm are too small to have accounted for the structures in Figure 2 (which are 20-40 nm). Second, the pattern of glycogen distribution illustrated in Figure 2 is consistent with what has been shown in previous ultrastructural studies (Peters and Palay, 1976
In the absence of glucose the glycogen content fell to a low, stable level by 30 min (see Fig. 3A), closely corresponding to the time at which axonal conduction failed. Glucose controls glycogen content by binding and inactivating the glycogen breakdown enzyme phosphorylase A (Stryer, 1995
Changes in RON glycogen content had significant functional consequences. Nerves with amplified glycogen stores maintained normal conduction for 12 min longer than did control nerves during glucose deprivation, and they showed much higher levels of CAP recovery after the insult. Moreover, CAP area never fell to zero in the high glycogen-containing nerves during aglycemia. In NE-treated nerves, with diminished glycogen, CAP recovery was less than in control nerves.
Our results supported the model shown in Figure 8. The model asserts that astrocytes contain glycogen, which is converted into lactate for transport to axons during glucose deprivation. Lactate is the most likely fuel to be transferred from astrocytes to axons for the following reasons: (1) astrocytes, but not neurons, are known to extrude large amounts of lactate (Walz and Mukerji, 1990
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Figure 8. Schematic illustration of how astrocytic glycogen appears to fuel axons in the absence of glucose. In the absence of glucose the astrocytic glycogen is broken down to lactate, which is transported to the extracellular space (ECS) via a MCT. Then it is taken up by a MCT in axons and is metabolized oxidatively to produce the energy needed to sustain excitability. LDH5 preferentially reduces pyruvate to lactate, and LDH1 preferentially oxidizes lactate to pyruvate. This scheme recognizes that astrocytes can subsist, at least transiently, on glycolytic energy metabolism, whereas axons require oxidative metabolism.
For astrocytes to convert glycogen to lactate for transfer to axons as a fuel in the absence of glucose (i.e., Fig. 8), several conditions must be met. There must be appropriate enzymes for the creation of lactate in astrocytes and for its use in axons, and there also must be appropriate transport mechanisms for lactate movement. Indeed, the expression patterns in the CNS of lactate dehydrogenase (LDH) and the monocarboxylate transporter (MCT) seem well suited to accommodate these needs. LDH, the enzyme catalyzing interconversion of pyruvate and lactate (Stryer, 1995
MCTs, of which there are several isoforms, shuttle lactate and pyruvate across cell membranes by using proton symport (Poole and Halestrap, 1993
The model is supported by the results of inhibiting lactate transport, which would be predicted to block the movement of lactate between astrocytes and axons. All three MCT blockers that were tested reduced CAP recovery after a 60 min period of glucose withdrawal. Quercetin preferentially inhibits lactate efflux from cells (Belt et al., 1979
The inhibitor 4-CIN can have effects on mitochondrial pyruvate transport (Juel and Halestrap, 1999
Our results support the idea that astrocytic glycogen acted as a readily available source of energy (i.e., lactate) for axons when glucose was withdrawn. This glial-neuronal interaction, although long a theoretical possibility and suggested by earlier tissue culture experiments (Swanson and Choi, 1993
FOOTNOTES Received April 19, 2000; revised June 27, 2000; accepted July 6, 2000.
This research was supported by National Institutes of Health Grants NS15589 (B.R.R.) and NS31914 (R.A.S.), and the Merit Review program of the Department of Veterans' Affairs (R.A.S.). R.W. was supported by National Institutes of Health Clinical Neurosciences Training Program T32 NS07144 (H. R. Winn). We thank Dr. Joel Black (Yale University) for generously providing the electron micrographs. R.W. thanks Dr. Thomas Möller (University of Washington) and Dr. H. Richard Winn (University of Washington, Department of Neurological Surgery) for helpful discussions.
Correspondence should be addressed to Dr. Bruce R. Ransom, Department of Neurology, Box 356465, University of Washington School of Medicine, Seattle, WA 98195. E-mail: bransom{at}u.washington.edu.
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