High-affinity plasma membrane GABA transporters GAT-1 and GAT-3 contribute to the modulation of GABA-mediated inhibition in adult mammalian cerebral cortex. How GATs regulate inhibition in neocortical circuits remains however poorly understood for the lack of information on key localizational features. In this study, we used quantitative pre- and post-embedding electron microscopy to define the distribution of GAT-1 and GAT-3 in elements contributing to synapses and to unveil their ultrastructural organization at adult cortical GABAergic synapses. GAT-1 and GAT-3 were found in both neuronal and astrocytic processes: GAT-1 was prevalently segregated in neuronal elements and in profiles contributing to synapses, whereas GAT-3 was mostly expressed in astrocytes and did not exhibit a preferential distribution in elements contributing to synapses. Analysis of the ultrastructural distribution of GAT-1 and GAT-3 in the plasma membrane of axon terminals and perisynaptic astrocytic processes of symmetric synapses in relation to the active zone revealed that GAT-1 was more concentrated in restricted perisynaptic and extrasynaptic regions, whereas GAT-3 was prominent in extrasynaptic areas. These studies provide a basis for understanding the role GAT-1 and GAT-3 play in the modulation of GABA-mediated phasic and tonic inhibition in cerebral cortex.
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