Table 2.

Some of the key evidence supporting the astrocyte–neuron lactate shuttle hypothesis

1.	Rate at which metabolized glucose enters the neuronal TCA cycle equals the rate of glial glutamate cycling (Sibson et al. 1998).
2.	In cultured mouse astrocytes (Pellerin & Magistretti, 1994) and glial Müller cells in retina (Poitry-Yamate et al. 1995), uptake of exogenous glutamate is strongly associated with increased La− production.
3.	Neuronal tissue can use La− as a fuel and may prefer it.
	a.	Studies on brain tissue, isolated nerves, and sympathetic ganglia have reported La− utilization in replacement of glucose (e.g. McIlwain, 1956; Carpenter, 1959; Brown et al. 2001).
	b.	La− can substitute for, or is preferred to, glucose, in cultured cortical neurons (Pellerin et al. 1998; Bouzier-Sore et al. 2003), chick sympathetic ganglia (e.g. Larrabee, 1995), vagus nerve (Véga et al. 1998), and photoreceptors in the retina (Poitry-Yamate et al. 1995) and human brain in vivo (Smith et al. 2003).
	c.	La− is metabolized through the TCA cycle in GABAergic and glutamatergic neurons with labelling of TCA cycle intermediates and several amino acids derived from cycle intermediates (Schousboe et al. 1997; Waagepetersen et al. 2000).
	d.	LDH1 is the predominant isoform of LDH in neurons and it has been argued that this isoform is more likely to convert La− to pyruvate because of its lower Km for La−. LDH5, the predominant isoform in astrocytes, is arguably more suited for pyruvate to La− conversion (e.g. Bittar et al. 1996; Pellerin et al. 1998).
	e.	Nuclear magnetic resonance spectroscopy has provided evidence of La− utilization as an energy substrate in brain tissue, specifically as a neuronal fuel (e.g. Hassel & Brathe, 2000; Qu et al. 2000).
4.	Glutamate is the primary excitatory neurotransmitter of the cerebral cortex. Some observations suggest a specific mechanism for detection of glutamatergic activity by astrocytic processes surrounding glutamatergic synapses, and a resulting La− production and release.
	a.	An α2 Na+–K+-ATPase is expressed together with glutamate transporters (GLT-1 and GLAST) in astrocytic processes surrounding glutamatergic synapses (e.g. Robinson & Dowd, 1997; Cholet et al. 2002).
	b.	Astrocytic glutamate transport is largely electrogenic with one glutamate molecule transported inward with three Na+ ions (Bouvier et al. 1992). Increased intracellular [Na+] stimulates astrocytic Na+–K+-ATPase (Kimelberg et al. 1993).
	c.	Mobilization of a ouabain-sensitive isoform, akin to the α2 Na+–K+-ATPase, appears responsible for the glutamate-uptake-stimulated aerobic glycolysis of cortical astrocytes (Pellerin & Magistretti, 1997).
	d.	Ouabain completely inhibits glutamate-evoked 2-deoxyglucose uptake by astrocytes (Pellerin & Magistretti, 1994).
	e.	Glial glutamate transporter knockout mice show reduced glucose utilization in the somatosensory cortex and cortical astrocytes from the same mice show abolition of glutamate-stimulated glucose utilization and La− production (Voutsinos-Porche et al. 2003).
5.	There is a cell-specific expression of monocarboxylate transporters (MCTs) in the central nervous system. In cultured mouse cortex preparations, MCT1 and MCT1 RNA are found almost exclusively in astrocytes while MCT2 and its RNA are exclusive to neurons. (Bröer et al. 1997; Debernardi et al. 2003). Adult rat brain cells show a similar pattern with MCT1 also present in endothelial cells of the blood–brain barrier (Mac & Nalecz, 2003).
6.	Neurons, but not glia, respond to La− with elevation of cytosolic ATP (Ainscow et al. 2002).
7.	Anatomical considerations suggest that astrocytes are an important intermediary between capillaries, neurons, and the synapses of the neurons (Magistretti & Pellerin, 1999).
	a.	In the brain, the entire surface of intraparenchymal capillaries is covered by specialized astrocytic end-feet (Peters et al. 1991).
	b.	Specialized astrocytic processes are wrapped around synaptic contacts (Rohlmann & Wolff, 1996; Bushong et al. 2002).
	c.	In most brain regions, the astrocyte:neuron ratio is 10: 1 (Bignami, 1991).

This table is derived heavily from Magistretti & Pellerin (1999), Chih et al. (2001), Bouzier-Sore et al. (2002) and Pellerin (2003).