Document Detail


Glut1 deficiency (G1D): epilepsy and metabolic dysfunction in a mouse model of the most common human phenotype.
MedLine Citation:
PMID:  22683290     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Isaac Marin-Valencia; Levi B Good; Qian Ma; Joao Duarte; Teodoro Bottiglieri; Christopher M Sinton; Charles W Heilig; Juan M Pascual
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't     Date:  2012-04-23
Journal Detail:
Title:  Neurobiology of disease     Volume:  48     ISSN:  1095-953X     ISO Abbreviation:  Neurobiol. Dis.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-08-06     Completed Date:  2013-01-14     Revised Date:  2013-10-17    
Medline Journal Info:
Nlm Unique ID:  9500169     Medline TA:  Neurobiol Dis     Country:  United States    
Other Details:
Languages:  eng     Pagination:  92-101     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
Affiliation:
Rare Brain Disorders Clinic and Laboratory, Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Brain / metabolism*,  physiopathology
Carbohydrate Metabolism, Inborn Errors / metabolism*,  physiopathology
Disease Models, Animal
Dopamine / metabolism
Epilepsy / metabolism*,  physiopathology
Fatty Acids / metabolism
Female
Glucose / metabolism
Glucose Transporter Type 1 / deficiency*
Male
Mice
Monosaccharide Transport Proteins / deficiency,  metabolism
Serotonin / metabolism
Grant Support
ID/Acronym/Agency:
1U24DK076174/DK/NIDDK NIH HHS; 5P41RR002584/RR/NCRR NIH HHS; F32 NS065640/NS/NINDS NIH HHS; F32NS065640/NS/NINDS NIH HHS; NS077015/NS/NINDS NIH HHS; P41 RR002584/RR/NCRR NIH HHS; R01 NS077015/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Fatty Acids; 0/Glucose Transporter Type 1; 0/Monosaccharide Transport Proteins; 0/Slc2a1 protein, mouse; 50-67-9/Serotonin; 50-99-7/Glucose
Comments/Corrections

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