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

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.

Paradoxical neuronal hyperexcitability in a mouse model of mitochondrial pyruvate import deficiency

“…However, upon release of the ‘brakes’ exerted by the inhibitory system, the neuro-MPC1-KO neurons would become hyperactive, which would translate into the observed epileptic output. Consistent with our data, mice deficient in pyruvate dehydrogenase (PDH), the enzyme acting immediately downstream of the MPC, were found to display an epileptiform cortical activity accompanied by behaviorally observable seizures( 45 ). In this case, the epileptiform activity occurred in the context of reduced background cortical activation and, as suggested by the authors, the most likely explanation was that seizures resulted from a combination of decreased activity of inhibitory neurons, mostly parvalbumin-expressing cortical neurons, with slightly overexcitable excitatory neurons.…”

“…Whole-cell patch clamp recordings were performed at nearly physiological temperature (30-32°C), with borosilicate pipettes (3-4 MΩ) filled with (in mM): 130 KGluconate, 10 KCl, 10 HEPES, 10 phosphocreatine, 0.2 EGTA, 4 Mg-ATP, 0.2 Na-GTP (290-300 mOsm, pH 7.2-7.3). A control experimental series was conducted with narrow pipettes tips (9-10 MΩ) filled with (in mM): 130 KGluconate, 5 KCl, 10 HEPES, 5 Sucrose (275-280 mOsm, pH 7.2-7.3), in order to delay intracellular dialysis( 45 ) and minimize interference with intracellular ATP and Ca 2+ levels. In this series, neuronal firing was measured within the first 1.5 min after whole-cell establishment (supplementary figure 8).…”

Ketogenic diet reduces alcohol withdrawal symptoms in humans and alcohol intake in rodents

“…Glucose metabolism, through the TCA cycle, is not only the main source of energy to the brain but is also the main carbon source for synthesis of glutamate and GABA ( 16 , 34 ). In preclinical models, reduced flux through the TCA results in reduced glutamate brain content and elicits epileptiform discharges, which are ameliorated by acetate administration ( 35 ). Thus, the increases in Glu and Glx that we observed with the KD are consistent with it helping to restore TCA flux and balancing excitatory and inhibitory neurotransmission.…”

Ketogenic Diet: A New Light Shining on Old but Gold Biochemistry

“…PDH DS can also be secondary to other defects such as deficiency of lipoid acid, an essential PDH cofactor [39], or depletion of mitochondrial Lon protease 1, involved in mitochondrial metabolism reprogramming upon stress signals [40]. Acetate administration has been shown to decrease the duration of seizure episodes in PDH deficient mice, suggesting a link between brain metabolism and the regulation of neuron excitability [41]. In addition, KD successfully improves seizures and neurologic outcomes of patients [42].…”