1.4 The Cerebral Tricarboxylic Acid Cycles

We review the operation of the cerebral tricarboxylic acid (TCA) cycles in the neuronal and glial compartments of the adult rat brain, with an emphasis on the mechanisms underlying intercellular oxidative coupling during glutamatergic neurotransmission. We begin with an update of the enzymatic properties, gene location, regulation, and regional distribution of the enzymes involved. Then, we describe the main methodologies used to investigate TCA cycle activity in vitro and in vivo such as autoradiography, positron emission tomography (PET), nuclear magnetic resonance (NMR) imaging or spectroscopy, and dual photon fluorescence microscopy. Previous interpretations conceived cerebral glucose metabolism during glutamatergic neurotransmission as a coupled process, involving exclusively anaerobic metabolism in the astrocytes and oxidative metabolism in the neurons. The glutamine cycle was proposed to be stoichiometrically coupled to astrocytic glucose uptake, glutamine synthesis being supported by astrocytic glycolysis only and glutamine being the main precursor of cerebral glutamate. Compelling evidences have accumulated since then, showing that astrocytes display significant oxidative capacity in vivo, more than 60% of the glutamine is produced from ATP synthesized by astroglial oxidative phosphorylation, and approximately 40% of cerebral glutamate is not derived from glutamine. Together, these findings suggest that the coupling mechanisms between astrocytic and neuronal oxidative and nonoxidative metabolisms are more complex than initially envisioned. In this review, we propose a novel mechanism based on the operation of intracellular redox switches and the transcellular coupling of the NAD(P)/NAD (P)H redox states between both cell types through lactate transfers. The redox switch/redox coupling hypothesis is compatible with the simultaneous operation of glycolytic and oxidative metabolisms in both neural cell types. Transcellular redox coupling through lactate transfers mimics the intracellular coupling existing between cytosolic NADH production and mitochondrial NADH oxidation, as seen from the redox shuttles exchanging reducing equivalents through the inner mitochondrial membrane of neural cells.This work was supported in part by grants SAF 2001‐224, SAF 2004‐03197, FISss C03/08, G03/155, C03/10 and PI051530 to S.C. JUSTESA IMAGEN S.A. provided the core support of LISMAR during this work. T.B. R was supported by a fellowship from Fundaçâo para a Ciência e Tecnologia, Portugal (SFRH/BD/5407/2001).Peer reviewe