Michael Sørensen

Synthesis of neurotransmitter GABA via the neuronal tricarboxylic acid cycle is elevated in rats with liver cirrhosis consistent with a high GABAergic tone in chronic hepatic encephalopathy

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Hepatic encephalopathy (HE) is a neuropsychiatric complication to liver disease. It is known that ammonia plays a role in the pathogenesis of HE and disturbances in the GABAergic system have been related to HE. Synthesis of GABA occurs by decarboxylation of glutamate formed by deamidation of astrocyte-derived glutamine. It is known that a fraction of glutamate is decarboxylated directly to GABA (referred to as the direct pathway) and that a fraction undergoes transamination with formation of alpha-ketoglutarate. The latter fraction is cycled through the neuronal tricarboxylic acid cycle, an energy-generating pathway, prior to being employed for GABA synthesis (the indirect pathway). We have previously shown that ammonia induces an elevation of the neuronal tricarboxylic acid cycle activity. Thus, the aims of the present study were to determine if increased levels of ammonia increase GABA synthesis via the indirect pathway in a rat model of HE induced by bile-duct ligation and in co-cultures of neurons and astrocytes exposed to ammonia. Employing (13) C-labeled precursors and subsequent analysis by mass spectrometry, we demonstrated that more GABA was synthesized via the indirect pathway in bile duct-ligated rats and in co-cultures subjected to elevated ammonia levels. Since the indirect pathway is associated with synthesis of vesicular GABA, this might explain the increased GABAergic tone in HE.
Original languageEnglish
JournalJournal of Neurochemistry
Volume117
Issue5
Pages (from-to)824-32
Number of pages9
ISSN0022-3042
DOIs
Publication statusPublished - 1 Jun 2011

    Research areas

  • Acetates, Ammonia, Animals, Astrocytes, Brain Chemistry, Chromatography, High Pressure Liquid, Chronic Disease, Citric Acid Cycle, Coculture Techniques, Common Bile Duct, Excitatory Amino Acids, Female, Hepatic Encephalopathy, Ligation, Liver Cirrhosis, Mass Spectrometry, Mice, Neurons, Neurotransmitter Agents, Rats, Rats, Wistar, gamma-Aminobutyric Acid

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