Differential expression of the GABA transporters GAT-1 and GAT-3 in brains of rats, cats, monkeys and humans

Abstract

The homeostasis of GABA is critical to normal brain function. Extracellular levels of GABA are regulated mainly by plasmalemmal gamma-aminobutyric acid (GABA) transporters. Whereas the expression of GABA transporters has been extensively studied in rodents, validation of this data in other species, including humans, has been limited. As this information is crucial for our understanding of therapeutic options in human diseases such as epilepsy, we have compared, by immunocytochemistry, the distributions of the GABA transporters GAT-1 and GAT-3 in rats, cats, monkeys and humans. We demonstrate subtle differences between the results reported in the literature and our results, such as the predominance of GAT-1 labelling in neurons rather than astrocytes in the rat cortex. We note that the optimal localisation of GAT-1 in cats, monkeys and humans requires the use of an antibody against the human sequence carboxyl terminal region of GAT-1 rather than against the slightly different rat sequence. We demonstrate that GAT-3 is localised mainly to astrocytes in hindbrain and midbrain regions of rat brains. However, in species such as cats, monkeys and humans, additional strong immunolabelling of oligodendrocytes has also been observed. We suggest that differences in GAT distribution, especially the expression of GAT-3 by oligodendrocytes in humans, must be accommodated in extrapolating rodent models of GABA homeostasis to humans.

Structure, function, and plasticity of GABA transporters

“…In rodents, the punctate immunostaining for GAT3 is localized exclusively in astrocytic processes scattered throughout the neuropil and adjacent to symmetric and asymmetric synapses close to cell bodies, basal and apical dendrites (Minelli et al, 1996; Ribak et al, 1996; Melone et al, 2005 but see Pow et al, 2005). In the brain of other mammalian species, like cats, monkeys and humans, the astrocyte-specific expression of GAT3 is lost, because here GAT3 is also expressed in oligodendrocytes (Pow et al, 2005).…”

Physiological bases of the K+ and the glutamate/GABA hypotheses of epilepsy

“…Contrary to glutamate, GABA is taken up by both presynaptic neurons and astrocytes via GATs (Pow et al, 2005). Thus, for example a decrease in neuronal GAT possibly implies reduced inhibitory GABAergic input (i.e.…”

Deletion of the GABAAReceptor α1 Subunit Increases Tonic GABAAReceptor Current: A Role for GABA Uptake Transporters

“…In the rodent cerebellum, GABA uptake is mediated by GAT-1 and GAT-3. GAT-1 expression is mostly localized to neurons, whereas GAT-3 is preferentially expressed in the glia (Itouji et al, 1996;Pow et al, 2005). NO711-sensitive GAT-1 fraction accounts for up to 85% of all GABA transport in wholecerebellum preparations (Chiu et al, 2005).…”