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

Vikram Jakkamsetti, Isaac Marin-Valencia, Qian Ma, Levi B. Good, Tyler Terrill, Karthik Rajasekaran, Kumar Pichumani, Chalermchai Khemtong, M. Ali Hooshyar, Chandrasekhar Sundarrajan, Mulchand S. Patel, Robert Bachoo, Craig R Malloy, Juan M Pascual

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Article numberaan0457
JournalScience Translational Medicine
Volume11
Issue number480
DOIs
StatePublished - Jan 1 2019

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Pyruvate Dehydrogenase Complex Deficiency Disease
Citric Acid Cycle
Brain
Glutamic Acid
Pyruvic Acid
Glucose
Electroencephalography
Oxidoreductases
Aminobutyrates
Vibrissae
Synaptic Transmission
Action Potentials
Neurotransmitter Agents
Epilepsy
Seizures
Acetates
Carbon
Neurons

ASJC Scopus subject areas

  • Medicine(all)

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Brain metabolism modulates neuronal excitability in a mouse model of pyruvate dehydrogenase deficiency. / Jakkamsetti, Vikram; Marin-Valencia, Isaac; Ma, Qian; Good, Levi B.; Terrill, Tyler; Rajasekaran, Karthik; Pichumani, Kumar; Khemtong, Chalermchai; Hooshyar, M. Ali; Sundarrajan, Chandrasekhar; Patel, Mulchand S.; Bachoo, Robert; Malloy, Craig R; Pascual, Juan M.

In: Science Translational Medicine, Vol. 11, No. 480, aan0457, 01.01.2019.

Research output: Contribution to journalArticle

Jakkamsetti, Vikram ; Marin-Valencia, Isaac ; Ma, Qian ; Good, Levi B. ; Terrill, Tyler ; Rajasekaran, Karthik ; Pichumani, Kumar ; Khemtong, Chalermchai ; Hooshyar, M. Ali ; Sundarrajan, Chandrasekhar ; Patel, Mulchand S. ; Bachoo, Robert ; Malloy, Craig R ; Pascual, Juan M. / Brain metabolism modulates neuronal excitability in a mouse model of pyruvate dehydrogenase deficiency. In: Science Translational Medicine. 2019 ; Vol. 11, No. 480.
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AU - Rajasekaran, Karthik

AU - Pichumani, Kumar

AU - Khemtong, Chalermchai

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AU - Sundarrajan, Chandrasekhar

AU - Patel, Mulchand S.

AU - Bachoo, Robert

AU - Malloy, Craig R

AU - Pascual, Juan M

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