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Sci Transl Med. 2019 Feb 20;11(480). pii: eaan0457. doi: 10.1126/scitranslmed.aan0457.

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

Author information

1
Rare Brain Disorders Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
2
Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
3
Laboratory of Developmental Neurobiology, The Rockefeller University, New York, NY 10065, USA.
4
Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
5
Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
6
Department of Mathematical Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA.
7
Department of Biochemistry, SUNY Buffalo, Buffalo, NY 14203, USA.
8
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
9
Rare Brain Disorders Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. juan.pascual@utsouthwestern.edu.
10
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
11
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
12
Eugene McDermott Center for Human Growth & Development / Center for Human Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

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.

PMID:
30787166
PMCID:
PMC6637765
[Available on 2020-02-20]
DOI:
10.1126/scitranslmed.aan0457

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