The GABA paradox: multiple roles as metabolite, neurotransmitter, and neurodifferentiative agent

GABA, which is present in the brain in large amounts, is distributed among distinctly different cellular pools, possibly reflecting its multiple functions as metabolite, neurotransmitter, and neurotrophin. Its metabolic enzymes also exhibit heterogeneity, because glutamate decarboxylase exists in two isoforms with different subcellular distribution and regulatory properties. Moreover, recent evidence points to a more pronounced regulatory role of the tricarboxylic acid cycle than hitherto anticipated in the biosynthetic machinery responsible for formation of GABA from glutamine. Additionally, GABAergic neurons may contain distinct populations of mitochondria having different turnover rates of the tricarboxylic acid cycle with different levels of association with GABA synthesis from 2-oxoglutarate via glutamate. These aspects are discussed in relation to the different functional roles of GABA and its prominent involvement in epileptogenic activity.