Review
GABA transporters in the mammalian cerebral cortex: localization, development and pathological implications

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Abstract

The extracellular levels of γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the mammalian cerebral cortex, are regulated by specific high-affinity, Na+/Cl dependent transporters. Four distinct genes encoding GABA transporters (GATs), named GAT-1, GAT-2, GAT-3, and BGT-1 have been identified using molecular cloning. Of these, GAT-1 and -3 are expressed in the cerebral cortex. Studies of the cortical distribution, cellular localization, ontogeny and relationships of GATs with GABA-releasing elements using a variety of light and electron microscopic immunocytochemical techniques have shown that: (i) a fraction of GATs is strategically placed to mediate GABA uptake at fast inhibitory synapses, terminating GABA's action and shaping inhibitory postsynaptic responses; (ii) another fraction may participate in functions such as the regulation of GABA's diffusion to neighboring synapses and of GABA levels in cerebrospinal fluid; (iii) GATs may play a role in the complex processes regulating cortical maturation; and (iv) GATs may contribute to the dysregulation of neuronal excitability that accompanies at least two major human diseases: epilepsy and ischemia.

Introduction

The amino acid γ-aminobutyric (GABA) is the main inhibitory neurotransmitter in the cerebral cortex, where it plays a fundamental role in controlling neuronal excitability and information processing [117], [118], [119], [136], [190], [194], [195], [196], [213], neuronal plasticity [7], [106], [200], and network synchronization [17], [27], [206].

Most neocortical GABA derives from aspiny nonpyramidal neurons whose axon terminals form symmetric synaptic contacts with both pyramidal and nonpyramidal cells [12], [46], [69], [88], [89], [93], [94], [106], [115], [173], [195]. GABAergic neurons are found in all cortical layers, they show a clear preference for layers IV and II–III, and account for 20–30% of all cortical neurons [11], [89]. Some GABA also appears to be released by extrinsic axons [4], [36], [67], [68], [70], [78], [81], [129], [207].

Several factors are involved in GABA's postsynaptic effects: presynaptic factors (release probability, number of release sites), factors acting at the cleft (diffusion and transporters), and postsynaptic factors (receptor subtypes, location, number, and interactions with anchoring proteins) [30]. Among those acting at the cleft, high-affinity plasma membrane GABA transporters (GATs) appear to modulate phasic [59], [64], [134], [205] and tonic [104], [184], [218] GABA-mediated inhibition and GABA spillover [10], [58], [60], [87], [101], [102], [120], [121], [146], [153], [177], [180], [209].

Four cDNAs encoding highly homologous GATs1 (GAT-1, GAT-2, GAT-3, and BGT-12) have been isolated in rodent and human nervous system [20], [21], [22], [34], [84], [122], [130], [148], [171]; they exhibit different ionic dependencies and inhibitor sensitivities, and are differentially distributed within the central nervous system [19], [44], [83], [110], [178], [182]. The first aim of this paper is to review the distribution and localization of GATs in the adult and developing cerebral cortex to gain insights into their functional roles.

GABA-mediated inhibition exerts a powerful control over cortical neuronal activity, and GABA transport contributes to modulate GABA's action. As altered GATs activity and/or expression are likely to affect markedly cortical function, the second aim of this paper is to provide a brief overview of their possible involvement in the pathophysiology of selected human diseases.

Section snippets

GAT-1

GAT-1 is the most copiously expressed GAT in the cerebral cortex. Its general distribution was first described in mapping studies [63], [100], [168], [202], [224], and subsequently detailed using in situ hybridization and light and electron microscopic techniques.

In situ hybridization studies in rat neocortex showed that the vast majority of cells expressing GAT-1 are neurons and that some are astrocytes [142]. Neurons expressing GAT-1 mRNA are widely distributed and are more numerous in layers

GAT-1

GAT-1 mRNA and protein first appear at late embryonic stages; their expression, weak in the neonatal cortex, gradually increases in the first two postnatal weeks [66], [107], [145], [219], [222]. Before birth, GAT-1 ir is restricted to the marginal zone (with the exception of the entorhinal cortex, where it is diffuse) [107]. At birth, GAT-1 ir is strong in outer layer I and light in the subplate. At P2, the signal increases in layer V and in the lower cortical plate, whereas the upper cortical

Expression of GATs in neurological diseases

This section does not address all the neuropsychiatric diseases in which changes in GABA transport have been described or could play a role. Rather, it is a succinct overview of the data linking the cortical expression of GATs to the few conditions in which such a role appears likely.

Comments and conclusions

Given its crucial role in the normal functioning of the cerebral cortex, an enormous research effort has been directed in the past decades at investigating GABAergic transmission. Most studies have focused on pre- and postsynaptic factors (in particular, GABA receptors), generating a vast body of data on their role in information processing and in the pathophysiology (and in some cases, the therapy) of human diseases. GATs studies are lagging behind, despite their obvious importance in cortical

Acknowledgements

We wish to thank all the colleagues who participated in the studies cited in the references for their fundamental contributions, Nick Brecha for introducing us to the field and for the GAT antibodies, Javier DeFelipe for his helpful comments on an early version of this paper, Robert Edwards for the VGAT antibodies, and Carlos Matute for the GABA antibodies. Personal work described here was supported by funds from MIUR (COFIN97, COFIN99, COFIN01) to F.C.

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    Present address: Istituto di Scienze Fisiologiche, Università di Urbino, Urbino, Italy.

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