TY - JOUR
T1 - Glut1 deficiency (G1D)
T2 - Epilepsy and metabolic dysfunction in a mouse model of the most common human phenotype
AU - Marin-Valencia, Isaac
AU - Good, Levi B.
AU - Ma, Qian
AU - Duarte, Joao
AU - Bottiglieri, Teodoro
AU - Sinton, Christopher M.
AU - Heilig, Charles W.
AU - Pascual, Juan M.
N1 - Funding Information:
We would like to acknowledge the assistance of Fundación Caja Madrid (IMV), NINDS F32NS065640 (LBG), NCRR 5P41RR002584 (JMP), NS077015 and the Dallas Women's Foundation (Billingsley Fund) (JMP), the Juvenile Diabetes Research Foundation ( 1-2004-698 ), Dialysis Clinics Inc. ( C-2957 ), and the American Diabetes Association ( 7-02-RA-34 ) (CWH). We also thank Drs. Craig R. Malloy for helpful discussions and Shawn Burgess for assistance with lipid determinations. The assistance of Drs. John Shelton and James Richardson (UT Southwestern Medical Center) with autoradiography experiments and of Drs. Michelle Puchowicz and Henri Brunengraber at the Case Western Reserve University National Mouse Metabolic Phenotyping Center (supported by NIDDK 1U24DK076174 ) and of Dr. Don Cooper (UT Southwestern Medical Center) with multielectrode recordings is also greatly appreciated.
PY - 2012/10
Y1 - 2012/10
N2 - 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 acetyl-CoA in the tricarboxylic acid (TCA) cycle. However, it is not known whether reduced brain glucose transporter type I (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 underexplored 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.
AB - 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 acetyl-CoA in the tricarboxylic acid (TCA) cycle. However, it is not known whether reduced brain glucose transporter type I (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 underexplored 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.
KW - Acetyl-coenzyme A
KW - Brain metabolism
KW - EEG
KW - Epilepsy
KW - Fatty acids
KW - GABA
KW - GLUT-1
KW - GLUT1
KW - Glucose transporter
KW - Glutamate
KW - Glutamine
KW - Ketones
KW - TCA cycle
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U2 - 10.1016/j.nbd.2012.04.011
DO - 10.1016/j.nbd.2012.04.011
M3 - Article
C2 - 22683290
AN - SCOPUS:84863827094
SN - 0969-9961
VL - 48
SP - 92
EP - 101
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 1
ER -