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.

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 epileptiform discharges, facilitating their prediction. Fast-spiking neuron excitability was decreased in brain slices, contributing to in vivo action potential burst prolongation after whisker pad stimulation. These features were partially reversed after systemic administration of acetate, which augmented cerebral TCA cycle flux, glutamate-dependent synaptic transmission, inhibition and gamma oscillations, and reduced epileptiform discharge duration. Thus, our results suggest that dysfunctional excitability in PDHD is consequent to reduced oxidative flux, which leads to decreased neuronal activation and impaired inhibition, and can be mitigated by an alternative metabolic substrate.

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