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

View Article: PubMed Central

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 (GYS1Nestin-KO) mouse to study the functional consequences of glycogen depletion in the brain under hypoxic conditions and susceptibility to epilepsy. GYS1Nestin-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, GYS1Nestin-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.

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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.
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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.

Mentions: We next analyzed the response of CA1 pyramidal neurons to paired pulses of increasing intensity presented to the ipsilateral Schaffer collaterals (Figures 2A,B). For ground-level conditions (top graphs), the two groups of mice presented an increase in the amplitude of fEPSPs evoked at the CA3–CA1 synapse in parallel with the increased intensity of the pulse applied, with significant facilitation to the second pulses at higher intensities. However, the excitability of the CA3–CA1 synapse differed between groups, with the GYS1Nestin-KO animals being more excitable than the control ones (Figure 2A). Thus, Control animals reached amplitudes of 0.49 ± 0.05 mV and 0.65 ± 0.08 mV at higher intensities for the first and second stimulus. In contrast, GYS1Nestin-KO mice reached 1.27 ± 0.3 mV and 1.38 ± 0.2 mV for the first and second stimulus. Exposure to hypobaric conditions caused an increase in the excitability of the CA3–CA1 synapse in both groups, as shown by a leftward displacement of the input/output curves. Although hypoxia increased the excitability in control mice at higher intensities, this was not observed in GYS1Nestin-KO, reaching maximum amplitudes after 60 min of hypobaric exposure (0.95 ± 0.3 mV and 1.0 ± 0.2 mV at higher intensities for the first and second stimulus for Control mice, and 1.38 ± 0.3 mV and 1.28 ± 0.2 mV for the first and second stimulus, respectively, for GYS1Nestin-KO animals (Figure 2A). Moreover, the differences detected between the St2/St1 ratios before the hypobaric exposure (1.27 ± 0.09 for Control vs 1.91 ± 0.26 for GYS1Nestin-KO mice, at 0.05 mA of intensity), and 15 min after its start (1.22 ± 0.15 for Control vs. 2.05 ± 0.32 for GYS1Nestin-KO mice, at 0.05 mA of intensity) were abolished after 60 min of hypoxia, recovering 24 h later, although at higher intensities (0.1 mA), reaching ratios of 1.35 ± 0.12 for Control vs. 2.06 ± 0.26 for GYS1Nestin-KO mice (Figure 2B).


Role of brain glycogen in the response to hypoxia and in susceptibility to epilepsy
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.
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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.
Mentions: We next analyzed the response of CA1 pyramidal neurons to paired pulses of increasing intensity presented to the ipsilateral Schaffer collaterals (Figures 2A,B). For ground-level conditions (top graphs), the two groups of mice presented an increase in the amplitude of fEPSPs evoked at the CA3–CA1 synapse in parallel with the increased intensity of the pulse applied, with significant facilitation to the second pulses at higher intensities. However, the excitability of the CA3–CA1 synapse differed between groups, with the GYS1Nestin-KO animals being more excitable than the control ones (Figure 2A). Thus, Control animals reached amplitudes of 0.49 ± 0.05 mV and 0.65 ± 0.08 mV at higher intensities for the first and second stimulus. In contrast, GYS1Nestin-KO mice reached 1.27 ± 0.3 mV and 1.38 ± 0.2 mV for the first and second stimulus. Exposure to hypobaric conditions caused an increase in the excitability of the CA3–CA1 synapse in both groups, as shown by a leftward displacement of the input/output curves. Although hypoxia increased the excitability in control mice at higher intensities, this was not observed in GYS1Nestin-KO, reaching maximum amplitudes after 60 min of hypobaric exposure (0.95 ± 0.3 mV and 1.0 ± 0.2 mV at higher intensities for the first and second stimulus for Control mice, and 1.38 ± 0.3 mV and 1.28 ± 0.2 mV for the first and second stimulus, respectively, for GYS1Nestin-KO animals (Figure 2A). Moreover, the differences detected between the St2/St1 ratios before the hypobaric exposure (1.27 ± 0.09 for Control vs 1.91 ± 0.26 for GYS1Nestin-KO mice, at 0.05 mA of intensity), and 15 min after its start (1.22 ± 0.15 for Control vs. 2.05 ± 0.32 for GYS1Nestin-KO mice, at 0.05 mA of intensity) were abolished after 60 min of hypoxia, recovering 24 h later, although at higher intensities (0.1 mA), reaching ratios of 1.35 ± 0.12 for Control vs. 2.06 ± 0.26 for GYS1Nestin-KO mice (Figure 2B).

View Article: PubMed Central

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 (GYS1Nestin-KO) mouse to study the functional consequences of glycogen depletion in the brain under hypoxic conditions and susceptibility to epilepsy. GYS1Nestin-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&ndash;CA1 synapse during experimentally induced hypoxia, thereby suggesting a compensatory switch to presynaptic mechanisms. Furthermore, GYS1Nestin-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.

No MeSH data available.


Related in: MedlinePlus