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. 2013 Jan 2;33(4):550–556. doi: 10.1038/jcbfm.2012.200

Impairment in long-term memory formation and learning-dependent synaptic plasticity in mice lacking glycogen synthase in the brain

Jordi Duran 1,2,5, Isabel Saez 1,3,5, Agnès Gruart 4, Joan J Guinovart 1,2,3, José M Delgado-García 4,*
PMCID: PMC3618391  PMID: 23281428

Abstract

Glycogen is the only carbohydrate reserve of the brain, but its overall contribution to brain functions remains unclear. Although it has traditionally been considered as an emergency energetic reservoir, increasing evidence points to a role of glycogen in the normal activity of the brain. To address this long-standing question, we generated a brain-specific Glycogen Synthase knockout (GYS1Nestin-KO) mouse and studied the functional consequences of the lack of glycogen in the brain under alert behaving conditions. These animals showed a significant deficiency in the acquisition of an associative learning task and in the concomitant activity-dependent changes in hippocampal synaptic strength. Long-term potentiation (LTP) evoked in the hippocampal CA3-CA1 synapse was also decreased in behaving GYS1Nestin-KO mice. These results unequivocally show a key role of brain glycogen in the proper acquisition of new motor and cognitive abilities and in the underlying changes in synaptic strength.

Keywords: brain glycogen, hippocampus, long-term potentiation, mice, operant conditioning

Introduction

The role of glycogen in the brain has been traditionally associated with the preservation of neuronal function during energetically challenging states such as hypoxia, hypoglycemia, or seizures. Nevertheless, glycogenolysis also occurs in euglycemia during an increase in neuronal activity, indicating that brain glycogen also has a role in supporting neuronal function in nonpathologic condition.1, 2, 3, 4 In this regard, glycogen concentration seems to be more conspicuous in areas of high synaptic density.5, 6

It has been proposed that the importance of brain glycogen lies in the rapidity of its breakdown compared with the uptake of extracellular glucose. During resting periods, glycogen pool would be replenished for further uses.7 This turnover could be crucial for learning and memory processes, where intense, energy-demanding increases in synaptic activity are required to induce the appropriate learning acquisition and storage mechanisms. Additionally, glycogen-derived pyruvate has been reported to be the preferred substrate for the de novo synthesis of glutamate.8, 9 Since glutamate-activated neurons are involved in learning consolidation,10 the relevance of glycogen in memory acquisition could go beyond mere energetic supply. Accordingly, several reports have described the importance of glycogenolysis for memory processing.11, 12

To unequivocally approach the study of the role of glycogen in the brain, here we generated a mouse model that lacks Glycogen Synthase specifically in the nervous system (GYS1Nestin-KO). We analyzed the learning capacity of these animals and checked for differences in the electrophysiologic properties of the hippocampal CA3-CA1 synapse. We also characterized the levels of glycogen-related proteins in this model. Our results show the important contribution of brain glycogen to associative learning and to the concomitant changes in hippocampal synaptic strength, as well as to the experimental induction of long-term potentiation (LTP) in hippocampal synapses.

Materials and methods

Generation of GYS1 Conditional Mice

The GYS1 knockout-first C57BL/6N cells were obtained from the International Knockout Mouse Consortium. The cells were injected into C57BL/6J blastocysts, which were implanted in pseudo-pregnant C57BL/6J females for the generation of chimeric mice. One chimeric male positive for the disruption was mated with C57BL/6J females to test for germline transmission. Heterozygous F1 mice were crossed with mice expressing Flp Recombinase to eliminate the selection cassette and to generate the conditional allele.

Animal Studies

Five-month-old male mice were used in these experiments. Experimental protocols were performed following European Union Council (2003/65/EU) and Spanish (BOE 252/34367-91, 2005) guidelines for the use of laboratory animals in chronic studies and in accordance with ARRIVE guidelines. All experimental protocols were also approved by the Ethics Committee of the Pablo de Olavide University.

Surgery

Mice were anesthetized with 0.8% to 1.5% isoflurane, supplied from a calibrated Fluotec 5 (Fluotec-Ohmeda, Tewksbury, MA, USA) vaporizer, at a flow rate of 1 to 2 L/min oxygen (AstraZeneca, Madrid, Spain) and delivered by a mouse anesthesia mask (David Kopf Instruments, Tujunga, CA, USA). Animals were implanted with bipolar stimulating electrodes in the right Schaffer collateral-commissural pathway of the dorsal hippocampus (2 mm lateral and 1.5 mm posterior to Bregma; depth from the brain surface, 1.0 to 1.5 mm) and with a recording electrode in the ipsilateral CA1 area (1.2 mm lateral and 2.2 mm posterior to Bregma; depth from the brain surface, 1.0 to 1.5 mm).13 These electrodes were made of 50-μm, Teflon-coated tungsten wire (Advent Research Materials, Eynsham, UK). The recording electrode was implanted in the CA1 area using as a guide the field potential depth profile evoked by paired (40-ms interval) pulses presented to the ipsilateral Schaffer collateral pathway. The recording electrode was fixed at the site where a reliable monosynaptic (⩽5 ms) field excitatory postsynaptic potential (fEPSP) was recorded. A bare silver wire was affixed to the skull as ground. Further details of these chronic preparations have been described elsewhere.14

Input/Output Curves, Paired-Pulse Facilitation and Long-Term Potentiation

For input/output curves, mice were stimulated at the hippocampal CA3-CA1 synapse with paired pulses (40 ms of interpulse interval) of increasing intensity (0.02 to 0.4 mA). Each pair of pulses was repeated ⩾5 times with time intervals ⩾30 seconds. For paired-pulse facilitation, we used pair of pulses of increasing intervals (10, 20, 40, 100, 200, and 500 ms) with intensity (in mA) fixed at ∼40% of the amount necessary to reach asymptotic values. Long-term potentiation was evoked in behaving mice following procedures described previously.14 Field EPSP baseline values were collected 15 minutes before LTP induction using single 100 μs square, biphasic pulses. Pulse intensity was set at ∼40% of the amount required to evoke a maximum fEPSP response (0.15 to 0.25 mA). For LTP induction, animals were presented with a high-frequency stimulation session. The high-frequency stimulation session consisted of five 200 Hz, 100 ms trains of pulses at a rate of 1/s repeated six times, at intervals of 1 minute. Thus, a total of 600 pulses were presented during each session of high-frequency stimulation. To avoid evoking large population spikes and the appearance of electroencephalographic seizures, the stimulus intensity during the high-frequency stimulation was set at the same as that used for generating baseline recordings. After the high-frequency stimulation session, the same single stimuli were presented every 20 seconds for 30 minutes and for the following 6 days.

Operant Conditioning

Training and testing were performed in Skinner box operant chambers. Before training, mice were handled daily for 7 days and food deprived to 80% of their free-feeding weight. Training took place for 20 minutes on successive days, in which mice learnt to press a lever to receive pellets from a food tray using a fixed-ratio (1:1) schedule. Field EPSPs evoked at the CA3-CA1 synapse were recorded during the training session. Stimuli were delivered at random (3 times/min), but for analysis only those presented when the animal was ready to press the lever were selected. A more complex conditioning task was performed for 11 days using a light/dark protocol, in which only during the lighted period was there a pellet reward. In addition, lever presses performed during the dark period restarted the dark protocol for additional time.15, 16

Biochemical Analyses

Animals were anesthetized and killed by decapitation. Brains were rapidly removed, frozen on liquid nitrogen and stored at −80°C until use. Total homogenates were analyzed for western blotting, and the determination of glycogen synthase activity and glycogen content as previously described.17

Immunohistochemistry

Five-month-old mice were anesthetized and perfused transcardiacally with phosphate-buffered saline (PBS) containing 4% (w/v) paraformaldehyde. Brains were removed, postfixed in the same solution overnight, cryoprotected with 30% (w/v) sucrose and sectioned at coronally planes (30 μℳ thick). For immunodetection of antigens, sections were washed in PBS and PBS-0.1% Triton X-100, blocked for 2 hours at room temperature with PBS containing 10% of normal goat serum and 0.2% of gelatin. Primary antibodies against GFAP (DAKO, Glostrup, Denmark), NeuN (Millipore, Billerica, MA, USA), calbindin and parvalbumin (Swant) were incubated overnight at 4°C with PBS-5% normal goat serum. Dye-labeled secondary antibodies and Hoechst 33342 were incubated for 2 hours at room temperature in 1 PBS-5% normal goat serum and mounted in Mowiol. Images were taken with a Nikon E1000 epifluorescence microscope (Nikon, Tokyo, Japan).

Data Analysis

Computed results were processed for statistical analysis using the IBM SPSS Statistics 18.0 (IBM, New York, NY, USA). Statistical significance of differences between groups was inferred by one-way ANOVA and ANOVA for repeated measures (data by groups), with a contrast analysis (Dunnett's post test) for a further study of significant differences. Statistical significance was set at P<0.05.

Results

Generation of a Brain-Specific GYS1 Knockout

In a first experimental step, we generated a conditional GYS1 allele that can be converted to a knockout (KO) allele by the action of a Cre Recombinase, which removes several exons of the gene (Figure 1A). To obtain a brain-specific GYS1 KO, we bred our conditional strain with Nestin-Cre transgenic mice to generate GYS1Nestin-KO mice. The nestin promoter induces Cre recombinase expression in neuronal and glia cell precursors by embryonic day 11.18 Homozygous conditional, non-Cre-expressing littermates were used as controls (Figure 1B). Deletion of GYS1 had no effect on the morphology of the brain, as shown by histologic analyses of different brain regions with neuronal and astrocytic markers (Supplementary Material).

Figure 1.

Figure 1

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Generation of a brain-specific Glycogen Synthase knockout (GYS1 KO). (A) Schematic representation of the alleles. The excision of the selection cassette from the knockout allele generates a conditional allele that expresses glycogen synthase normally. The subsequent excision of several exons from the conditional allele by a Cre Recombinase generates again a knockout allele. (B) Genotypes used in the study. Homozygous conditional, non-Cre-expressing littermates were used as controls of GYS1Nestin-KO. (C) Western blot of glycogen synthase in total homogenates of brain and skeletal muscle using an antibody that recognizes specifically the muscle (MGS) or the liver isoform (LGS). Mouse liver extract (L) was used as a positive control for LGS. Actin was used as a loading control. (D) Total glycogen synthase activity in the presence of its allosteric activator Glucose 6-phosphate (P=2.80 × 10−7). (E) Glycogen levels (P=0.007) in brain extracts of control and GYS1Nestin-KO mice. Control (n=4), KO (n=4). *Statistically significant (P⩽0.05).

Analyses of brain extracts by western blot confirmed that GYS1Nestin-KO mice are devoid of muscle Glycogen Synthase (MGS; Figure 1C). To rule out the possibility of the induction of the liver isoform of Glycogen Synthase to compensate for the absence of MGS, we analyzed liver isoform of Glycogen Synthase levels with a liver isoform-specific antibody, finding no expression. We also confirmed that our model is a brain-specific KO, as MGS levels in the skeletal muscle were equivalent in control and GYS1Nestin-KO animals. As expected, Glycogen Synthase activity and glycogen levels were null in the brain extracts of GYS1Nestin-KO mice (Figures 1D and 1E). These results prove that MGS is the only enzyme that synthesizes glycogen in the brain.

Analysis of the Levels of Proteins Involved in Glycogen Metabolism in the GYS1Nestin-KO Mouse Brain

To study the impact of the absence of glycogen on the proteins involved in its metabolism, we analyzed changes in their expression by western blot (Figure 2) in total brain homogenates. Glycogen Phosphorylase isoforms expressed in the brain—brain and muscle isoforms—, total α/β and phosphorylated (inactive) β Glycogen Synthase Kinase 3 (GSK3 α/β and pGSK3 β, respectively) were unchanged. Contrary, glycogen debranching enzyme levels were decreased and AMP kinase (AMPK) increased in the GYS1Nestin-KO brain (Figure 2A). In the case of AMPK, the levels of the phosphorylated (active) form (pAMPK) were unchanged. Glycogenin western blotting under normal conditions requires a previous treatment of the sample with amylase to digest the glycogen and thus free the protein so that it can be detected by the antibody.19 In the case of GYS1Nestin-KO samples, however, glycogenin was detectable even without amylase treatment (Figure 2B). Equivalent results were obtained when analyzing changes in all proteins in isolated hippocampi (Supplementary Material).

Figure 2.

Figure 2

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Changes in the expression of proteins involved in glycogen metabolism in the GYS1Nestin-KO mouse brain. (A) MGS, brain and muscle isoforms of Glycogen Phosphorylase (BGPh and MGPh, respectively), glycogen debranching enzyme (GDE), AMP kinase (AMPK), pAMPK, GSK3 α/β, and pGSK3 β were analyzed in total brain homogenates. (B) Glycogenin levels were analyzed in untreated and amylase-treated total brain extracts. Actin was used as a loading control.

Differences in the Electrophysiologic Properties of the CA3-CA1 Synapse

To analyze the functional consequences of glycogen deficiency, we measured the response of hippocampal pyramidal CA1 neurons to paired pulses presented to the ipsilateral Schaffer collaterals in alert, behaving control and GYS1Nestin-KO mice (Figure 3A). For this purpose, we first recorded the responses to paired pulses of increasing intensity. Both groups presented similar increases in the slope of fEPSPs evoked by the first pulse. These increases were best fitted by sigmoid curves (r⩾0.99; P<0.0001), suggesting a normal functioning of the CA3-CA1 synapse in GYS1Nestin-KO mice. Nevertheless, KO mice presented a larger facilitation to the second pulse than control mice (Figure 3B). Paired-pulse facilitation was further analyzed at a wide range of interpulse intervals. Interestingly, GYS1Nestin-KO mice presented a significantly larger facilitation to paired pulses than control animals, especially at short interpulse intervals (F(5,10)=5.141; P<0.001; Figure 3C).

Figure 3.

Figure 3

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Electrophysiologic changes of hippocampal synapses in GYS1Nestin-KO alert behaving mice. (A) Experimental design. Animals were chronically implanted with stimulating electrodes in the hippocampal Schaffer collaterals and with a recording electrode in the ipsilateral pyramidal CA1 area. An extra wire was attached to the bone as ground (DG, dentate gyrus; Sub., subiculum). (B) Input/output curves of field excitatory postsynaptic potentials (fEPSPs) evoked by paired pulses of increasing intensities in control (n=11) and knockout (KO) (n=11) mice. The best nonlinear adjustments to the collected data are illustrated. (C) Paired-pulse facilitation analyses (mean±s.e.m. slopes of the second fEPSP expressed as a percentage of the first interpulse interval). Representative fEPSP paired traces (40 ms of interpulse interval) are shown on the right. Control (n=11), KO (n=11). (D) Time course of long-term potentiation (LTP) evoked in the CA3-CA1 synapse after a high-frequency stimulation (HFS) session (mean±s.e.m. fEPSP slopes given as a percentage of values collected during baseline recordings (100%)). Control (n=7), KO (n=7). Representative examples of fEPSPs collected at the indicated times are plotted at the top. *Statistically significant (P<0.05) differences between the two groups.

We next studied the LTP capabilities of the two animal groups. Long-term potentiation is widely considered to be the cellular basis of learning and memory.20 After the high-frequency stimulation session, only the control group presented a significant LTP for the first recording day (F(44,264)=9.504; P<0.001; Figure 3D). The GYS1Nestin-KO mice did not present any evident sign of LTP (P⩾0.927) and even they showed a nonsignificant (P⩾0.879) depotentiation phenomenon during the subsequent recording days (Figure 3D). In addition, LTP values collected from controls were significantly (P<0.05, see asterisks in Figure 3D) larger and longer lasting than those collected from GYS1Nestin-KO mice. To discard a change in the levels of N-methyl-𝒟-aspartate receptor (NMDAR) which could explain these differences, we analyzed the NR1 subunit of NMDA receptor (NMDAR1) by western blot and found no significant (P>0.05) differences between the two groups. N-methyl-𝒟-aspartate receptor forms a heterodimer of at least one NR1 and one NR2A-D subunit. Thus, by analyzing NMDAR1 subunit we addressed all possible combinations (see Supplementary Material). Thus, the deficit in LTP generation observed in GYS1Nestin-KO mice could be ascribed to the unavailability of brain glycogen.

Impairment in the Acquisition of an Instrumental Conditioning Task and in the Associated Changes in Synaptic Strength

To further explore the role of brain glycogen, a highly demanding associative learning task (operant conditioning) was tested. Mice were trained in Skinner box modules to obtain a food pellet by pressing a lever located near the feeder (Figure 4A). In the first series of experiments, animals were rewarded with a food pellet every time the lever was pressed (fixed-ratio (1:1) schedule; Figure 4B, top diagram). Control animals reached the selected criterion—to press the lever a minimum of 20 times/session for two successive 20-minute sessions—earlier than GYS1Nestin-KO mice (F(6,72)=4.629; P<0.001; Figure 3C). The mean number of days needed (Figure 4D) and the percentage of mice reaching the selected criterion (Figure 4E) were also significantly different between groups. As already described, a proper functioning of hippocampal synaptic circuits is required for the acquisition of associative learning tasks.14, 15 Accordingly, the analysis of fEPSPs evoked at the hippocampal CA3-CA1 synapse during the learning process showed a significantly larger change in synaptic strength in controls when compared with values collected from GYS1Nestin-KO mice (Figure 4F).

Figure 4.

Figure 4

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Impaired performance of GYS1Nestin-KO mice in an operant conditioning task. (A) Experimental set-up. Mice were trained in a Skinner box to press a lever to obtain a food pellet. (B) Two tasks of increasing difficulty were assayed. In task 1 (fixed-ratio (1:1)), mice received a food pellet each time they pressed the lever. In task 2 (Light/Dark), lever presses were rewarded only when a light bulb was switched on. Pressing the lever during the dark period punished the animal with an additional delay in the reappearance of the light period. (C) Lever presses in the first 7 days of training of task 1. Dotted line corresponds to criterion. (D) Mean days required to reach the criterion. (E) Percentage of mice reaching the criterion during the training. (F) Evolution of field excitatory postsynaptic potential (fEPSPs) evoked at the CA3-CA1 synapse during task 1 (mean±s.e.m. fEPSP slopes given as a percentage of values collected before training (100%)). (G) Performance of control and GYS1Nestin-KO mice during task 2. Control (CT) (n=13), KO (n=13). *Statistically significant (P<0.01) differences between the two groups.

In a second series of experiments, animals that had reached the criterion, for the fixed-ratio (1:1) schedule, within 7 days were further trained in a more complex situation, in which they were rewarded only during the period in which a small light bulb was switched on (Figure 4B, bottom diagram). Pressing the lever during the dark period punished the animal with an additional delay in the reappearance of the lighted period. Again, control mice acquired this task faster than GYS1Nestin-KO animals, reaching significant (F(10,120)=5.438; P<0.01) differences by the tenth and eleventh training sessions (Figure 4G). In fact, GYS1Nestin-KO did not reach the selected criterion (see dotted line in Figure 4G).

Discussion

Here, we report for the first time on a mouse model lacking glycogen specifically in the brain. The use of a genetic model presents clear advantages over previous studies based on drug treatments, such as nonspecificity or uncontrolled side effects. Additionally, the tissue specificity of the gene deletion, as shown by the unaltered levels of Glycogen Synthase in the skeletal muscle, has allowed us to selectively study the involvement of brain glycogen in learning and memory processes.

We first studied how the lack of glycogen regulates the proteins related to its metabolism. Only glycogen debranching enzyme and AMPK showed changes in their protein levels, thus suggesting that their regulation is directly dependent on the presence of the glycogen molecule. Interestingly, the levels of phosphorylated AMPK remained unchanged, thereby pointing to a cellular compensation mechanism to maintain AMPK activity constant. Glycogenin was detectable in GYS1Nestin-KO samples even without amylase treatment thereby further confirming the absence of glycogen. The difference in the mobility of glycogenin before and after amylase treatment may correspond to glycosyl units attached to the glycogenin protein by self-glycosylation.21

We next analyzed the functional consequences of the absence of brain glycogen. The histologic analysis of GYS1Nestin-KO brain discarded developmental problems which could be on the base of the results obtained. Importantly, we performed electrophysiologic studies in alert, behaving animals, following procedures developed by some of us.14, 15, 22 Our results show that paired-pulse facilitation, a well-characterized form of short-term plasticity related to short-term memory processes, is in fact enhanced in GYS1Nestin-KO mice. Paired-pulse stimulation is frequently used as an indirect measurement of changes in the probability of neurotransmitter release at the presynaptic terminal.23, 24, 25 It is assumed that any change in the response evoked by the second stimulus in relation to the first is indicative of a presynaptic action, while changes evoked simultaneously by both pulses are indicative of a postsynaptic effect.26 Our findings thus reflect a disturbance in the release of neurotransmitters at the presynaptic terminal in GYS1Nestin-KO mice. As recently shown in alert behaving mice,27 this type of short-term modulation of synaptic strength can have a homeostatic role in the proper functioning of hippocampal circuits.28 In this regard, the absence of appropriated postsynaptic LTP responses, presented by GYS1Nestin-KO mice, is compensated in those animals by an increase in short-term presynaptic plasticity. As a whole, the present results are in accordance with previous reports pointing to a role for glycogen as a precursor of glutamate29 and describing its importance in short-term memory processes.11

However, LTP has been proposed as the cellular mechanism underlying the acquisition of new motor and cognitive abilities.14, 20, 30 Remarkably, GYS1Nestin-KO mice did not show any significant LTP after the presentation of the high-frequency stimulation session. As LTP acquisition implies high energy consumption, these results suggest that the availability of glycogen as a rapid energy source is crucial to evoke this long-lasting change in synaptic strength. The importance of brain glycogen could rely on the rapidity of its breakdown compared with uptake and phosphorylation of glucose. Indeed, the first step of glycolysis is glucose phosphorylation by Hexokinase, which is one of the slowest enzymes of the glycolytic pathway. Brain glycogen, in contrast, is metabolized by Glycogen Phosphorylase, a fast enzyme, generating glucose-6-phosphate. Thus, glycogen may provide supplemental fuel to support function when energy obtained from extracellular glucose is insufficient.7

Operant conditioning is a highly demanding associative learning task involving the participation of many cortical areas linked to spatial orientation, object recognition, coordinated motor responses, and cognitive processes relating ongoing behavior with its putative reward consequences. As already reported15, 16 and confirmed here, these analyses can be performed in mice when lever and feeder are adapted to their sizes. Results collected from the Skinner box show that the lack of brain glycogen results in a significant impairment in the learning process, as already suggested by the impairment in the experimental induction of LTP.

Overall, here we have shown that the lack of Glycogen Synthase, and thus of glycogen in the brain, produces a significant deficit in learning capacity and in the concomitant activity-dependent changes in synaptic strength. These observations unequivocally show the key role of brain glycogen in the proper and timed acquisition of relatively difficult learning tasks. This is the first time that the contribution of glycogen to learning has been unambiguously proven by means of genetic tools in alert behaving conditions. These findings may have relevant implications for the treatment of selective learning- and memory-related disorders.

Acknowledgments

The authors thank María Sánchez-Enciso and Natàlia Plana for their technical assistance. Thanks also go to Stephen Forrow for advice and Tanya Yates for correcting the English manuscript.

The authors declare no conflict of interest.

Footnotes

Supplementary Information accompanies the paper on the Journal of Cerebral Blood Flow & Metabolism website (http://www.nature.com/jcbfm)

This work was supported by grants from the Spanish MINECO (BFU2011-29089, BFU2011-29286, and BFU2011-30554) to AG, JMD-G, and JJG, the Junta de Andalucía (BIO122, CVI 2487, and P07-CVI-02686) and the European Community's Seventh Framework Program (FP7/2007-2013) under grant agreement n° 201714 (DEVANX) to AG and JMD-G, the CIBER de Diabetes y Enfermedades Metabólicas Asociadas (ISCIII, Ministerio de Ciencia e Innovación), the Human Frontiers Science Program (RGP0027/2011), and the Marcelino Botín Foundation to JJG.

Supplementary Material

Supplementary Information
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