Abstract
The extracellular levels of γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the cerebral cortex, are regulated by specific high-affinity Na+/Cl− dependent plasma membrane transporters. Three GABA transporters (GATs), named GAT-1, GAT-2, and GAT-3 appear to play an important role in determining GABA’s effects. Studies on the distribution, cellular and subcellular localization, ontogeny, relationships of GATs with GABA-releasing elements using a variety of light and electron microscopic immunocytochemical techniques, as well as on their physiological effects performed over the last 25 years in our laboratory have contributed to unveil their organizational plan and at least some of their physiological roles. Although many details are missing, the anatomy and physiology of the cortical GABA uptake system in the adult (and developing) cerebral cortex appears to be sufficiently understood to allow the study of its dynamic physiological features, as well as its role in neuropsychiatric diseases.
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Notes
- 1.
The term “transporter” is used here to indicate high-affinity plasma membrane transporters, and should not be confounded with vesicular transporters.
- 2.
We use the nomenclature of Guastella et al. [16] and Borden [2] and refer to cDNA clones from rat (r) brain. An analogous, though not identical, nomenclature introduced by Liu et al. [23] identifies cDNA clones from mouse (m) brain encoding four GATs and names them GAT1–GAT4. Whereas mGAT1 is the homolog of rGAT-1, mGAT2, mGAT3, and mGAT4 appear to be the homologs of dog BGT-1, rGAT-2 and rGAT-3, respectively. In addition, rGAT-3 is identical to a rat clone designated as GAT-B by [5].
- 3.
A popular view is that a modest neuronal depolarization results in GAT-1 reversal, which would determine non-vesicular GABA release into the extracellular space during intense network activity. By combining a kinetic model of GAT-1 with experimental measurements of tonic GABAAR currents in hippocampal slices, Savtchenko and colleagues [32] provided convincing evidence that sustained efflux of GABA through GAT-1 is unlikely to occur during physiological or pathological.
- 4.
Whether BGT-1 (for Betaine/GABA Transporter) or its mouse or human homologs contribute to GABA transport in the brain remains to be determined (see Borden [2], for a detailed description of the discovery, homologies, and pharmacological properties of BGT-1).
- 5.
See Scimeni [34] for a model-based view of the differential properties of synaptic and extrasynaptic GATs.
References
Axelrod J (1970) Noradrenaline: fate and control of its biosynthesis. Nobel Lecture. https://www.nobelprize.org/uploads/2018/06/axelrod-lecture.pdf
Borden LA (2006) GABA transporter heterogeneity: pharmacology and cellular localization. Neurochem Int 29:335–356
Bragina L, Marchionni I, Omrani A, Cozzi A, Pellegrini-Giampietro DE, Cherubini E, Conti F (2008) GAT-1 regulates both tonic and phasic GABAA receptor-mediated inhibition in the cerebral cortex. J Neurochem 105:1781–1793
Cherubini E, Conti F (2001) Generating diversity at GABAergic synapses. Trends Neurosci 24:155–162
Clark JA, Deutch AY, Gallipoli PZ, Amara S (1992) Functional expression and CNS distribution of a β-alanine-sensitive neuronal GABA transporter. Neuron 9:337–348
Conti F, Minelli A, Brecha NC (1994) Cellular localization and laminar distribution of AMPA glutamate receptor subunits mRNAs and proteins in the rat cerebral cortex. J Comp Neurol 350:241–259
Conti F, Minelli A, Molnar M, Brecha NC (1994) Cellular localization and laminar distribution of NMDAR1 mRNA in the rat cerebral cortex. J Comp Neurol 343:554–565
Conti F, Melone M, De Biasi S, Ducati A, Minelli A, Brecha NC (1998) Neuronal and glial localization of GAT-1, a high-affinity GABA plasma membrane transporter, in the human cerebral cortex. J Comp Neurol 396:51–63
Conti F, Vitellaro-Zuccarello L, Barbaresi P, Minelli A, Brecha NC, Melone M (1999) Neuronal, glial, and epithelial localization of γ-aminobutyric acid transporter-2, a high-affinity γ-aminobutyric acid plasma membrane transporter, in the cerebral cortex and neighboring structures. J Comp Neurol 409:482–494
Conti F, Minelli A, Melone M (2004) GABA transporters in the mammalian cerebral cortex: localization, development and pathological implications. Brain Res Rev 45:196–212
Conti F (2010) Fisiologia Medica. Edi-Ermes, Milano
Conti F, Melone M, Fattorini G, Bragina L, Ciappelloni S (2011) A role for GAT-1 in presynaptic GABA homeostasis? Front Cell Neurosci 5:2
Farrant M, Nusser Z (2005) Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors. Nat Rev Neurosci 6:215–229
Fattorini G, Melone M, Sánchez-Gómez MV, Arellano RO, Bassi S, Matute C, Conti F (2017) GAT-1 mediated GABA uptake in rat oligodendrocytes. Glia 65:514–522
Fattorini G, Catalano M, Melone M, C Serpe, Bassi S, Limatola C, Conti F (2019) Microglial expression of GAT-1 in the cerebral cortex. Glia (in press). https://doi.org/10.1002/glia.23745
Guastella J, Nelson N, Nelson H, Czyzyk L, Keynan S, Miedel MC, Davidson N, Lester HA, Kanner BI (1990) Cloning and expression of a rat brain GABA transporter. Science 249:1303–1306
Kandel ER, Schwartz JH, Siegelbaum SA, Hudspeth AJ (2013) Principles of neural science. McGraw Hill Medical, New York
Kanner BI (1978) Active transport of gamma-aminobutyric acid by membrane vesicles isolated from rat brain. Biochemistry 17:1207–1211
Keynan S, Suh Y-J, Kanner BI, Rudnick G (1992) Expression of a cloned y-aminobutyric acid transporter in mammalian cells. Biochemistry 31:1974–1979
Kinjo A, Koito T, Kawaguchi S, Inoue K (2013) Evolutionary history of the GABA transporter (GAT) group revealed by marine invertebrate GAT-1. PLoS ONE 8:e82410
Krnjevic K (1984) Neurotransmitters in cerebral cortex: a general account. In: Peters A, Jones EG (eds) cerebral cortex, vol 2. Functional properties of cortical cells. New York, Plenum, pp 39–61
Iversen L (2006) Neurotransmitter transporters and their impact on the development of psychopharmacology. Br J Pharmacol 147:S82–S88
Liu Q-R, Lopez-Corcuera B, Mandiyan S, Nelson H, Nelson N (1993) Molecular characterization of four pharmacologically distinct γ-aminobutyric acid transporters in mouse brain. J Biol Chem 268:2106–2112
Melone M, Cozzi A, Pellegrini-Giampietro DE, Conti F (2003) Transient focal ischemia triggers neuronal expression of GAT-3 in the rat perilesional cortex. Neurobiol Dis 14:120–132
Melone M, Barbaresi P, Fattorini G, Conti F (2005) Neuronal localization of the GABA transporter GAT-3 in human cerebral cortex: a procedural artifact? J Chem Neuroanat 30:45–54
Melone M, Ciappelloni S, Conti F (2014) Plasma membrane transporters GAT-1 and GAT-3 contribute to heterogeneity of GABAergic synapses in neocortex. Front Neuroanat 8:72
Melone M, Ciappelloni S, Conti F (2015) A quantitative analysis of cellular and synaptic localization of GAT-1 and GAT-3 in rat neocortex. Brain Struc Funct 220:885–897
Minelli A, Brecha NC, Karschin C, DeBiasi S, Conti F (1995) GAT-1, a high-affinity GABA plasma membrane transporter, is localized to neurons and astroglia in the cerebral cortex. J Neurosci 15:7734–7746
Minelli A, DeBiasi S, Brecha NC, Conti F (1996) GAT-3, a high affinity GABA plasma membrane transporter, is localized exclusively to astrocytic processes in the cerebral cortex. J Neurosci 16:6255–6264
Minelli A, Alonso-Nanclares L, Edwards RH, DeFelipe J, Conti F (2003) Postnatal development of the vesicular GABA transporter in rat cerebral cortex. Neuroscience 117:337–346
Minelli A, Barbaresi P, Conti F (2003) Postnatal development of high-affinity plasma membrane GABA transporters GAT-2 and GAT-3 in the rat cerebral cortex. Dev Brain Res 142:7–18
Savtchenko L, Megalogeni M, Rusakov DA, Walker MC, Pavlov I (2015) Synaptic GABA release prevents GABA transporter type-1 reversal during excessive network activity. Nat Commun 6:6597
Scimemi A (2014a) Structure, function, and plasticity of GABA transporters. Front Cell Neurosci 8:161
Scimemi A (2014b) Plasticity of GABA transporters: an unconventional route to shape inhibitory synaptic transmission. Front Cell Neurosci 8:128
Torres GE, Gainetdinov RR, Caron MG (2003) Plasma membrane monoamine transporters: structure, regulation and function. Nat Rev Neurosci 4:13–25
Acknowledgements
The research project on GABA transporters was initiated in a fantastic and unforgettable Californian summer (1992), devoted to an in situ hydridization study of glutamate receptors subunits in Nick Brecha’s lab [6, 7]. One afternoon, Nick showed me the first slides with brain sections stained with a new antibody raised (by him and Catia Sternini) against the recently cloned GABA transporter (GAT-1), and insisted to start a collaboration on its localization in the brain (I shall never thank Nick enough for insisting). After some resistance, I accepted. From that day onwards, a GABA transporter project has always been ongoing in the lab. And from that day onwards, Nick has been one of my most valued colleagues, and, most importantly, one of my dearest friends.
The work described here would not have been possible without the continuous financial support of national and international agencies. I am therefore highly indebted to the Ministry of University and Research (PRIN programs for the years 1997, 1999, 2001, 2003, 2005, 2008, 2010/2011, and 2015), Telethon (1998), CNR (1992 and 1995), NATO (1993), Stanley Foundation/NAMI Research Institute (1998 and 2001), Giorgini Foundation (2004, 2011, and 2017), and—last but not least—to UNIVPM, my beloved Alma Mater.
Many collaborators, post-docs, and students have much contributed to these studies. They are listed below (with the affiliation at the time of the collaboration), and I warmly thank to all of them.
Lidia Alonso-Nanclares (Cajal Institute, Madrid)
Rogelio O. Arellano (UPV/EHU University of the Basque Country, Bilbao)
Paolo Barbaresi (UNIVPM)
Silvia Bassi (UNIVPM)
Luca Bragina (UNIVPM)
Myriam Catalano (Sapienza University of Rome)
Enrico Cherubini (SISSA, Trieste)
Silvia Ciappelloni (UNIVPM)
Andrea Cozzi (University of Florence)
Silvia DeBiasi (University of Milan)
Javier DeFelipe (Cajal Institute, Madrid)
Alessandro Ducati (UNIVPM)
Robert H Edwards (USF, San Francisco)
Giorgia Fattorini (UNIVPM)
Christine Karschin (UCLA, Los Angeles)
Cristina Limatola (Sapienza University of Rome)
Ivan Marchionni (SISSA, Trieste)
Carlos Matute (UPV/EHU University of the Basque Country, Bilbao)
Marcello Melone (UNIVPM)
Andrea Minelli (UNIVPM)
Azar Omrani (SISSA, Trieste)
Domenico E Pellegrini-Giampietro (University of Florence)
Maria Victoria Sánchez-Gómez (UPV/EHU University of the Basque Country, Bilbao)
Laura Vitellaro-Zuccarello (University of Milan)
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Conti, F. (2020). A 25 Years-Long Journey with GABA Transporters. In: Longhi, S., et al. The First Outstanding 50 Years of “Università Politecnica delle Marche”. Springer, Cham. https://doi.org/10.1007/978-3-030-33832-9_11
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