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Volume 16, Number 19, Issue of October 1, 1996 pp. 6255-6264
Copyright ©1996 Society for Neuroscience

GAT-3, a High-Affinity GABA Plasma Membrane Transporter, Is Localized to Astrocytic Processes, and It Is Not Confined to the Vicinity of GABAergic Synapses in the Cerebral Cortex

Andrea Minelli¹, Silvia DeBiasi², Nicholas C. Brecha^{3, 4, 5, 6, 7}, Laura Vitellaro Zuccarello², and Fiorenzo Conti¹

¹ Institute of Human Physiology, University of Ancona, I-60131 Ancona, Italy; ² Department of General Physiology and Biochemistry, Section of Histology and Human Anatomy, University of Milan, 20133 Milan, Italy; ³ Department of Neurobiology, ⁴ Department of Medicine, ⁵ Brain Research Institute, and ⁶ CURE: Digestive Diseases Research Center, UCLA School of Medicine; and ⁷ Veterans Administration Medical Center, Los Angeles, California 90073

The termination of GABA synaptic action by high-affinity, Na⁺-dependent, neuronal, and glial plasma membrane transporters plays an important role in regulating neuronal activity in physiological and pathological conditions. We have investigated the cellular localization and distribution in the cerebral cortex of adult rats of one GABA transporter (GAT), GAT-3, by immunocytochemistry with affinity-purified polyclonal antibodies directed to its predicted C terminus that react monospecifically with a protein of ~70 kDa.

Light microscopic studies revealed specific GAT-3 immunoreactivity (ir) in small punctate structures, and it was never observed in fibers or cell bodies. No changes in immunostaining were observed in sections incubated with GAT-3 antibodies preadsorbed with the related rat GAT-1 or mouse GAT-2/BGT-1 C-terminal peptides, whereas in sections incubated with GAT-3 antibodies preadsorbed with rat GAT-3 C-terminal peptide, ir was not present. The highest number of GAT-3-positive puncta was in layer IV and in a narrow band corresponding to layer Vb, followed by layers II and III. Many GAT-3-positive puncta were in close association with pyramidal and nonpyramidal neuron cell bodies. Ultrastructural studies showed that GAT-3 ir was localized exclusively to astrocytic processes, which were found in the neuropil and adjacent to axon terminals having either symmetric or asymmetric specializations. In sections processed by both preembedding labeling for GAT-3 and postembedding immunogold labeling for GABA, only some of the GAT-3-positive astrocytic processes were found close to GABAergic profiles.

These findings on the localization of GAT-3 in the cerebral cortex indicate that this transporter mediates GABA uptake into glial cells, and suggest that glial GABA uptake may function to limit the spread of GABA from the synapse, as well as to regulate overall GABA levels in the neuropil.

Key words: synaptic transmission; GABA; GABA transporters; neocortex; symmetric and asymmetric synapses; astrocytes

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