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

Abstract

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.

Heptanoate as a Neural Fuel: Energetic and Neurotransmitter Precursors in Normal and Glucose Transporter I-Deficient (G1D) Brain

“…It has been reported that GLUT-1 deficiency induces reactive astrocytosis, 39 defined as an increase in the number and the size of cells expressing glial fibrillary acidic protein. 40 Reactive astrocytes that retain expression of glutamine synthetase are present in the brain of G1D mice, 14 consistent with a greater rate of glutamine synthesis from heptanoate in G1D relative to normal brain.…”

“…**Po0.01,***Po0.001. normal, which correlates with the presence of reactive astrocytes with preserved expression of glutamine synthetase in the G1D brain, probably as a potential compensatory mechanism of glucose transporter deficiency in these cells, 14 No differences were identified in the levels of glutamate or GABA across animal groups. The concentration of succinate, fumarate, and malate was also equivalent between both animal groups.…”

“…Normal C57BL/6J mice (n ¼ 4, weight ¼ 21.5±0.6 g, age ¼ 4.2±0.2 months; all ranges and errors hereafter are expressed as standard error of the mean (s.e.m.) unless otherwise indicated) and transgenic GLUT-1 mice (n ¼ 6, weight: 17.9 ± 3.5 g, age: 3.1 ± 0.3 months) 14 were used for the study. A cannulation and infusion protocol was used as previously described.…”

A Cause of Permanent Ketosis: GLUT-1 Deficiency

“…Marin-Valencia et al have shown in a mouse GLUT-1-deficiency model that total blood ketone bodies were markedly increased with normal blood glucose concentrations in a non-fasting state. This implies that GLUT-1-deficiency mice exhibit ketosis that can constitute a metabolic adaptation (Marin-Valencia et al 2012). …”

Study of the genetic basis of dystonia in Serbian population

“…metode kod bolesnika uočen poremećen metabolizam glukoze u kortikostrijatalnim putevima (Weber et al, 2008;Suls et al, 2008). Sa druge strane, eksperimenti vršeni na GLUT1-DS mišijem modelu (primenom antisense GLUT-1) pokazuju da se nivo dopamina i serotonin, kao i produkata njihovog metabolizma, u korteksu, talamusu i striatumu ne razlikuje u odnosu na kontrolne miševe (Marin Valencia et al, 2012).…”