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. 2015 Oct 27:9:431.
doi: 10.3389/fncel.2015.00431. eCollection 2015.

Role of brain glycogen in the response to hypoxia and in susceptibility to epilepsy

Juan C López-Ramos  1 , Jordi Duran  2 , Agnès Gruart  1 , Joan J Guinovart  3 , José M Delgado-García  1
Affiliations

Role of brain glycogen in the response to hypoxia and in susceptibility to epilepsy

Juan C López-Ramos et al. Front Cell Neurosci. .

Abstract

Although glycogen is the only carbohydrate reserve of the brain, its overall contribution to brain functions remains unclear. It has been proposed that glycogen participates in the preservation of such functions during hypoxia. Several reports also describe a relationship between brain glycogen and susceptibility to epilepsy. To address these issues, we used our brain-specific Glycogen Synthase knockout (GYS1(Nestin-KO)) mouse to study the functional consequences of glycogen depletion in the brain under hypoxic conditions and susceptibility to epilepsy. GYS1(Nestin-KO) mice presented significantly different power spectra of hippocampal local field potentials (LFPs) than controls under hypoxic conditions. In addition, they showed greater excitability than controls for paired-pulse facilitation evoked at the hippocampal CA3-CA1 synapse during experimentally induced hypoxia, thereby suggesting a compensatory switch to presynaptic mechanisms. Furthermore, GYS1(Nestin-KO) mice showed greater susceptibility to hippocampal seizures and myoclonus following the administration of kainate and/or a brief train stimulation of Schaffer collaterals. We conclude that brain glycogen could play a protective role both in hypoxic situations and in the prevention of brain seizures.

Keywords: brain glycogen; epilepsy; hypobaric hypoxia; kainate; local field potentials; mice.

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Figures

FIGURE 1
FIGURE 1
Spectral analysis of local field potentials (LFPs) recorded in the pyramidal CA1 area from the two groups of mice in different hypobaric situations. (A) Experimental design. Animals were implanted with recording (Rec.) electrodes in the hippocampal CA1 area and with stimulating (St.) electrodes in the ipsilateral Schaffer collateral-commissural pathway. (B,E) From top to bottom are illustrated LFPs recorded and sequenced power spectra (1–5 Hz, 6–10 Hz, 11–20 Hz, and 21–50 Hz) from representative wild-type (WT) and GYS1Nestin-KO (KO) mice placed at ground level (35 m ≈ 760 mmHg) (B), 15 min (C) and 60 min (D) after being placed under hypobaric conditions (5000 m ≈ 405 mmHg), and 24 h after being returned to ground level (760 mmHg; 24 h) (E). Note the different LFP profiles presented by the two groups of mice in the four different hypobaric situations. Calibrations in (E) are also for (B–D). Spectral analysis was averaged from LFPs recorded from n ≥ 10 animals per group. Note the higher spectral powers computed from KO mice in the 6–10 Hz band for the two hypobaric situations when compared with those presented by their littermate controls. Amplitudes of power spectra were normalized taking the sum of the total power spectra (from 1 to 50 Hz) of each animal during the initial 760 mmHg situation as a total power (PWR) of 100. Values are expressed as mean ± SEM. Statistical differences, ∗P < 0.05. Student t-test.
FIGURE 2
FIGURE 2
Electrophysiological changes of hippocampal synapses in GYS1Nestin-KO behaving mice under hypobaric conditions. (A) Input/output curves of fEPSPs evoked by paired pulses (40 ms of inter-stimulus interval) of increasing intensities (0.02–0.2 mA) in wild-type (A, WT; n = 8) and GYS1Nestin-KO (B, KO; n = 10) mice. The first and the second fEPSPs are represented. Note that the hypobaric situation increased fEPSP amplitudes, mainly in controls and in GYS1Nestin-KO mice for fEPSPs evoked by the second pulse at lower intensities. Dotted lines were set at the maximum values reached by WT animals under the initial ground-level conditions (≈0.5 mV). (B) St2/St1 ratios of the fEPSPs showed in (A). The initial significant differences between ratios were abolished after 60 m of hypobaric exposure, and recovered 24 h after it, at higher intensities. Values are expressed as mean ± SEM. Triangles in (A) represent differences between firsts (black) and second (white) fEPSPs, P < 0.05. Differences between ratios, ∗P < 0.05; ∗∗P < 0.01. Student t-test.
FIGURE 3
FIGURE 3
Electrophysiological changes of hippocampal synapses in GYS1Nestin-KO behaving mice under hypobaric conditions. (A) Paired-pulse facilitation of fEPSPs evoked by a pair of pulses at ≈40% of the maximum intensity and at different inter-pulse intervals (10, 20, 40, 100, 200, and 500 ms) in wild-type (WT; n = 12) and GYS1Nestin-KO (KO; n = 10) mice. The amplitudes of fEPSPs evoked by the first pulse and the second are represented for the two groups of mice. Note that GYS1Nestin-KO mice presented a larger facilitation (∗) to the second pulse for short intervals (10–100 ms) at ground level than did controls, and that the hypobaric conditions evoked a noticeable increase in the amplitude of fEPSPs evoked by the two pulses, although abolished the significant differences between groups. Dotted lines were set at the maximum values reached by WT animals under the initial ground-level conditions (≈0.45 mV). (B) St2/St1 ratios of the fEPSPs showed in (A). The initial significant differences between ratios were abolished during the hypobaric exposure, and recovered 24 h after it. Values are expressed as mean ± SEM. Statistical differences, ∗P < 0.05; ∗∗P < 0.01. Student t-test.
FIGURE 4
FIGURE 4
Effects of kainate injection on spontaneous LFPs recorded from the two groups of mice. (A) Representative examples of LFPs recorded from a wild-type (WT) mouse before and 30 min after a kainate injection (8 mg/kg, i.p.). (B) Spectral analysis of hippocampal LFP recordings collected from a representative WT mouse before (continuous trace) and after (dotted trace) kainic injection. (C,D) Same set of data collected from a representative GYS1Nestin-KO (KO) mouse. Note that the presence of repetitive (≈2–3 Hz) clonic seizures (C) significantly (P < 0.05) increased the amplitude of the power spectrum (dotted line in D). (E,F) LFP recordings (E) and spectral power analysis (F) of a tonic seizure evoked in a KO animal by the kainate injection. Note that the long-lasting seizure (dotted line in F) canceled out (before vs. after, P < 0.001) the normal theta rhythm (black line in F) present in hippocampal LFP recordings. Also note that the spectral power increased significantly (P < 0.001) in different (5–10 and 10–15 Hz) frequency bands during the seizure (gray line in F). One-way ANOVA.
FIGURE 5
FIGURE 5
Effects of kainate injection and train stimulation in GYS1Nestin-KO behaving mice. (A,B) Representative fEPSPs evoked at the hippocampal CA3–CA1 synapse of a wild-type (A, WT) and a GYS1Nestin-KO (B, KO) animal before and after kainate injection (8 mg/kg, i.p.). Note that the presence of clonic seizures significantly reduced the amplitude of the evoked fEPSP in the KO mouse. (C,D) Effects on fEPSPs of train stimulation (10 Hz) of the hippocampal CA3–CA1 synapse in a wild-type (C, WT) and a GYS1Nestin-KO (D, KO) animal during tonic-clonic seizures. Records were collected before and after a kainate injection that evoked seizures only in the KO mouse. Note that the presence of spontaneous seizures evoked by kainate injection decreased the amplitude of fEPSPs evoked by train stimulation. (E–G) Differential effects of train stimulation (arrows: five 200 Hz, 100 ms trains of pulses at a rate of 1/s) of WT and KO mice before and after kainate injection. Note the long-lasting seizure evoked in the KO animal even before kainate injection (G). In all cases, intensity of train stimulation was set at ≈40% of that necessary to evoke a maximum response during the input/output test. (H,I) Percentage (%) of WT (n = 16) and KO (n = 14) mice presenting seizures following train stimulation before (H) and after (I) kainate injection.
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