Research ArticlePYRUVATE DEHYDROGENASE DEFICIENCY

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

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Science Translational Medicine  20 Feb 2019:
Vol. 11, Issue 480, eaan0457
DOI: 10.1126/scitranslmed.aan0457

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An alternative energy source for PDHD

Pyruvate dehydrogenase deficiency (PDHD) is a rare disorder caused by altered glucose metabolism. The symptoms of PDHD are predominantly neurological, and patients develop intractable epilepsy early in infancy. However, the mechanisms responsible for the increased brain excitability are mostly unknown. To address this issue, Jakkamsetti et al. developed a mouse model of PDHD recapitulating the neurological symptoms of the human disease. The authors found that seizure activity was mediated by reduction of the mitochondrial tricarboxylic acid (TCA) cycle flux and decreased excitability in a population of putative inhibitory neurons. Administration of acetate, an alternative metabolic substrate, restored TCA activity and reduced seizure duration.

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