Brain metabolism modulates neuronal excitability in a mouse model of pyruvate dehydrogenase deficiency

Science Translational Medicine
Vikram JakkamsettiJuan M Pascual

Abstract

Glucose is the ultimate substrate for most brain activities that use carbon, including synthesis of the neurotransmitters glutamate and γ-aminobutyric acid via mitochondrial tricarboxylic acid (TCA) cycle. Brain metabolism and neuronal excitability are thus interdependent. However, the principles that govern their relationship are not always intuitive because heritable defects of brain glucose metabolism are associated with the paradoxical coexistence, in the same individual, of episodic neuronal hyperexcitation (seizures) with reduced basal cerebral electrical activity. One such prototypic disorder is pyruvate dehydrogenase (PDH) deficiency (PDHD). PDH is central to metabolism because it steers most of the glucose-derived flux into the TCA cycle. To better understand the pathophysiology of PDHD, we generated mice with brain-specific reduced PDH activity that paralleled salient human disease features, including cerebral hypotrophy, decreased amplitude electroencephalogram (EEG), and epilepsy. The mice exhibited reductions in cerebral TCA cycle flux, glutamate content, spontaneous, and electrically evoked in vivo cortical field potentials and gamma EEG oscillation amplitude. Episodic decreases in gamma oscillations preceded most...Continue Reading

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Citations

Oct 20, 2019·Nutrients·Raffaella LongoMaurizio Crestani
Jun 13, 2021·Progress in Neurobiology·Shuai ZhangXiaofeng Jia
Jul 12, 2021·Annals of Clinical and Translational Neurology·Mackenzie CervenkaAdam L Hartman
Jul 15, 2021·Scientific Reports·Vikram JakkamsettiJuan M Pascual
Aug 11, 2021·Cell Metabolism·Sojeong JunMichalis Agathocleous
Dec 3, 2021·Biological Trace Element Research·Li ZhangLixiang Liu

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