Glut1 deficiency (G1D): Epilepsy and metabolic dysfunction in a mouse model of the most common human phenotype

NEUROBIOLOGY OF DISEASE

卷:48

Article

Marin-Valencia, Isaac¹  Good, Levi B.¹  Ma, Qian¹  Duarte, Joao²  Bottiglieri, Teodoro³  Sinton, Christopher M.⁴  Heilig, Charles W.⁵  Pascual, Juan M.^1,6,7 

[1] Univ Texas SW Med Ctr Dallas, Dept Neurol & Neurotherapeut, Rare Brain Disorders Clin & Lab, Dallas, TX 75390 USA

[2] Univ Texas SW Med Ctr Dallas, Adv Imaging Res Ctr, Dallas, TX 75390 USA

[3] Baylor Univ, Med Ctr, Inst Metab Dis, Waco, TX 76798 USA

[4] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA

[5] Univ Florida, Coll Med, Div Nephrol, Gainesville, FL 32611 USA

[6] Univ Texas SW Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA

[7] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA

关键词: Epilepsy;    Brain metabolism;    TCA cycle;    Acetyl-coenzyme A;    Glutamate;    Glutamine;    GABA;    GLUT1;    GLUT-1;    Glucose transporter;    Ketones;    Fatty acids;    EEG;   

DOI  :  10.1016/j.nbd.2012.04.011

来源: Elsevier

【 摘 要 】

Brain glucose supplies most of the carbon required for acetyl-coenzyme A (acetyl-CoA) generation (an important step for myelin synthesis) and for neurotransmitter production via further metabolism of acetylCoA in the tricarboxylic acid (TCA) cycle. However, it is not known whether reduced brain glucose transporter type! (GLUT-1) activity, the hallmark of the GLUT-1 deficiency (G1D) syndrome, leads to acetyl-CoA. TCA or neurotransmitter depletion. This question is relevant because, in its most common form in man, G1D is associated with cerebral hypomyelination (manifested as microcephaly) and epilepsy, suggestive of acetyl-CoA depletion and neurotransmitter dysfunction, respectively. Yet, brain metabolism in G1D remains under-explored both theoretically and experimentally, partly because computational models of limited brain glucose transport are subordinate to metabolic assumptions and partly because current hemizygous G1D mouse models manifest a mild phenotype not easily amenable to investigation. In contrast, adult antisense G1D mice replicate the human phenotype of spontaneous epilepsy associated with robust thalamocortical electrical oscillations. Additionally, and in consonance with human metabolic imaging observations, thalamus and cerebral cortex display the lowest GLUT-1 expression and glucose uptake in the mutant mouse. This depletion of brain glucose is associated with diminished plasma fatty acids and elevated ketone body levels, and with decreased brain acetyl-CoA and fatty acid contents, consistent with brain ketone body consumption and with stimulation of brain beta-oxidation and/or diminished cerebral lipid synthesis. In contrast with other epilepsies, astrocyte glutamine synthetase expression, cerebral TCA cycle intermediates, amino acid and amine neurotransmitter contents are also intact in G1D. The data suggest that the TCA cycle is preserved in G1D because reduced glycolysis and acetyl-CoA formation can be balanced by enhanced ketone body utilization. These results are incompatible with global cerebral energy failure or with neurotransmitter depletion as responsible for epilepsy in G1D and point to an unknown mechanism by which glycolysis critically regulates cortical excitability. (C) 2012 Elsevier Inc. All rights reserved.

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