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Brain metabolism modulates neuronal excitability in a mouse model of pyruvate
dehydrogenase deficiency.
Authors Jakkamsetti V, Marin-Valencia I, Ma Q, Good LB, Terrill T, Rajasekaran K,
Pichumani K, Khemtong C, Hooshyar MA, Sundarrajan C, Patel MS, Bachoo RM, Malloy
CR, Pascual JM
Submitted By Submitted Externally on 8/6/2019
Status Published
Journal Science translational medicine
Year 2019
Date Published 2/1/2019
Volume : Pages 11 : Not Specified
PubMed Reference 30787166
Abstract Glucose is the ultimate substrate for most brain activities that use carbon,
including synthesis of the neurotransmitters glutamate and ?-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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