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

Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101505086 Publication Model: Print Cited Medium: Internet ISSN: 1946-6242 (Electronic) Linking ISSN: 19466234 NLM ISO Abbreviation: Sci Transl Med Subsets: MEDLINE

Original Publication: Washington, DC : American Association for the Advancement of Science

Brain/*metabolism ; Neurons/*physiology ; Pyruvate Dehydrogenase Complex Deficiency Disease/*metabolism ; Pyruvate Dehydrogenase Complex Deficiency Disease/*physiopathology; Acetates/metabolism ; Algorithms ; Animals ; Carbon Isotopes ; Cerebral Cortex/metabolism ; Disease Models, Animal ; Electroencephalography ; Evoked Potentials ; Gamma Rhythm ; Glucose/metabolism ; Glutamic Acid/metabolism ; Humans ; Machine Learning ; Mice ; Neural Inhibition ; Seizures/metabolism ; Seizures/physiopathology ; Vibrissae

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.
(Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

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R01 NS102588 United States NS NINDS NIH HHS; R01 NS077015 United States NS NINDS NIH HHS; K08 NS110877 United States NS NINDS NIH HHS; P41 EB015908 United States EB NIBIB NIH HHS; U24 DK076174 United States DK NIDDK NIH HHS

0 (Acetates)
0 (Carbon Isotopes)
3KX376GY7L (Glutamic Acid)
FDJ0A8596D (Carbon-13)
IY9XDZ35W2 (Glucose)

Date Created: 20190222 Date Completed: 20200221 Latest Revision: 20241118

20241118

PMC6637765

10.1126/scitranslmed.aan0457

30787166