Localization and Function of GABA Transporters GAT-1 and GAT-3 in the Basal Ganglia

Xiao-Tao Jin, Adriana Galvan, Thomas Wichmann, Yoland Smith, Xiao-Tao Jin, Adriana Galvan, Thomas Wichmann, Yoland Smith

Abstract

GABA transporter type 1 and 3 (GAT-1 and GAT-3, respectively) are the two main subtypes of GATs responsible for the regulation of extracellular GABA levels in the central nervous system. These transporters are widely expressed in neuronal (mainly GAT-1) and glial (mainly GAT-3) elements throughout the brain, but most data obtained so far relate to their role in the regulation of GABA(A) receptor-mediated postsynaptic tonic and phasic inhibition in the hippocampus, cerebral cortex and cerebellum. Taking into consideration the key role of GABAergic transmission within basal ganglia networks, and the importance for these systems to be properly balanced to mediate normal basal ganglia function, we analyzed in detail the localization and function of GAT-1 and GAT-3 in the globus pallidus of normal and Parkinsonian animals, in order to further understand the substrate and possible mechanisms by which GABA transporters may regulate basal ganglia outflow, and may become relevant targets for new therapeutic approaches for the treatment of basal ganglia-related disorders. In this review, we describe the general features of GATs in the basal ganglia, and give a detailed account of recent evidence that GAT-1 and GAT-3 regulation can have a major impact on the firing rate and pattern of basal ganglia neurons through pre- and post-synaptic GABA(A)- and GABA(B)-receptor-mediated effects.

Keywords: GABA transporter; globus pallidus; patch clamp recording; striatum; substantia nigra.

Figures

Figure 1
Figure 1
Tonic activation of presynaptic GABABRs induced by GAT-1 blockade in rat brain slices. (A) eIPSCs in response to paired-pulse stimulation (ISI 250 ms) in control solution and in the presence of the GAT-1 blocker, NO-711 (10 μm), in slices of P12-14 rats. Traces represent averages of 20 responses. (B) Quantification of results for NO-711 effects on the mean eIPSC amplitude, PPR (PPR50: ISI 50 ms, PPR250: ISI 250 ms), rise time (20–80%) and decay (T0.10) of striatal eIPSC. Data from 17 striatal output neurons (SONs), except PPR50. (C) Evoked IPSCs in response to paired-pulse stimulation (ISI 250 ms) in control solution and in the presence of either NO-711 or NO-711 plus the GABAB-receptor antagonist CGP55845 (1 μm). Traces represent averages of 20 responses. (D,E) CGP55845 partially restored the NO-711-induced reduction in eIPSC amplitude and completely reversed the NO-711-induced increase in PPR (ISI 250 ms). ns – not significant, *P < 0.05, **P < 0.01, ***P < 0.001. Reprinted from Kirmse et al. (2008) with permission from John Wiley and Sons.
Figure 2
Figure 2
Functional expression of GAT-2/3 is unmasked by suppression of GAT-1 activity in the rat striatum. (A) Sample traces showing mIPSCs in the presence of NO-711 (10 μM) and NO-711 plus SNAP 5114 (40 μM) in striatal slices of P12–14 rats. (B) Cumulative mIPSCs amplitude distribution was not significantly affected by SNAP 5114 (P > 0.9, Kolmogorov–Smirnov test). Plot represents data from the cell shown in (A). (C) SNAP 5114 – selectively decreased the frequency of mIPSCs. *P < 0.05. Reprinted from Kirmse et al. (2009) with permission from John Wiley and Sons.
Figure 3
Figure 3
Light and electron micrographs of GAT-1 and GAT-3-immunoreactive elements in the rat and monkey globus pallidus. (A,B) Light micrographs of GAT-1 and GAT-3 labeling in the rat striatum (STR) and globus pallidus (GP). (C) GAT-1-immunoreactive axon terminal (Te) and astrocytic process (AS) in the rat GP. Note that the labeled terminal forms a symmetric synapse (arrowhead) with an unlabeled dendrite. (D) GAT-3-positive astrocytic processes in close contact with unlabeled terminals and dendrites in the rat GP. (E) Quantification of the percentage of GAT-1- and GAT-3-labeled elements in the rat GP. Note that GAT-1 is predominantly found in unmyelinated axons, whereas GAT-3 is mainly expressed in glial processes. A total of three rats were used in these studies (see Jin et al., , for details). (F,G) GAT-1 and GAT-3 immunoreactivity in the monkey putamen (Put) and globus pallidus (external and internal segments, GPe, GPi). (H) GAT-1-immunoreactive unmyelinated axons (AX) and astrocytic processes (AS) in the monkey GPe. Note that the labeled AS is in close contact with an unlabeled terminal (u.TE) that forms an axo-dendritic symmetric synapse [arrowhead; (I,J)] GAT-3-positive astrocytes in the monkey GPe (I) and GPi (J). Note the close association between the immunoreactive AS processes and unlabeled axon terminals forming symmetric synapses [arrowheads in (I)]. (K) Quantitative distribution of GAT-1 and GAT-3 across different neuronal and glial elements in the monkey GPe and GPi (see Galvan et al., , for more details). Scale bars: (A,B,F,G): 1 mm; (C,D,H,I,J): 1 μm.
Figure 4
Figure 4
Effects of SKF 89976A and SNAP 5114 on GABA levels in GPe and pallidal discharge rate in monkeys. (A) Dialyzate samples were collected every 10 min. SKF 89976A or SNAP 5114 were administered during sample 4 (horizontal bar). Data area means ± SD from three experiments for each treatment in a single monkey. Difference from ACSF experiments (Mann–Whitney UU test): *P < 0.05. (B1) Example of effect of SKF 89976A on discharge rate of a GPe cell. (B2) Discharge rate of GPe and GPi cells during baseline period and at the point of maximal effect of SKF 89976A. (C1) The discharge rate of this GPe cell is inhibited after administration of the GAT-3 blocker, SNAP 5114. (C2) The discharge rate of GPe and GPi cells during baseline period and at the point of maximal effect of SNAP 5114 injection. In (B1,C1), horizontal bars indicate duration of drug infusions. Dashed lines represent mean discharge rate ± 2 SD. For more details see Galvan et al. (2005).
Figure 5
Figure 5
Effects of GAT-1 and GAT-3 blockade on GABAergic and glutamatergic synaptic transmission in the rat GP. (A) Application of SKF 89976A increases the decay time, but not the amplitude of IPSCs evoked in GP neurons after striatal stimulation. (B) Bar graph showing that SKF 89976A increases the decay time, but has no effect on the amplitude and base line holding currents of eIPSCs expressed as percent of control ± SEM (*P < 0.005). (C) Application of SNAP 5114 increases the amplitude and decay time of IPSCs evoked in GP neuron by striatal stimulation. (D) Bar graph summarizing the effects of SNAP 5114 on eIPSCs amplitude, decay time, and holding current expressed as percent of control ± SEM (*P < 0.005). (E,F). Sample traces showing mEPSCs recorded in control condition and during SKF 89976A or SNAP 5114 application. (G,H) The summary bar graphs show that SKF 89976A or SNAP 5114 significantly reduce the frequency, but not amplitude of mEPSCs. * P < 0.01. For more details see Jin et al. (2009, 2011).

References

    1. Ade K. K., Janssen M. J., Ortinski P. I., Vivini S. (2008). Differential tonic GABA conductances in striatal medium spiny neurons. J. Neurosci. 28, 1185–119710.1523/JNEUROSCI.3908-07.2008
    1. Allen N. J., Karadottir R., Attwell D. (2004). Reversal or reduction of glutamate and GABA transport in CNS pathology and therapy. Eur. J. Physiol. 449, 132–14210.1007/s00424-004-1318-x
    1. Augood S. J., Herbison A. E., Emson P. C. (1995). Localization of GAT-1 GABA transporter mRNA in rat striatum: cellular coexpression with GAD67 mRNA, GAD67 immunoreactivity and parvalbumin mRNA. J. Neurosci. 15, 865–874
    1. Augood S. J., Waldvogel H. J., Munkle M. C., Faull R. L. M., Emson P. C. (1999). Localization of calcium-binding proteins and GABA transporter (GAT-1) messenger RNA in the human subthalamic nucleus. Neuroscience 88, 521–53410.1016/S0306-4522(98)00226-7
    1. Bahena-Trujillo R., Arias-Montano J. A. (1999). [3H] gamma-aminobutyric acid transport in rat substantia nigra pars reticulate synaptosomes: pharmacological characterization and phorbol ester-induced inhibition. Neurosci. Lett. 274, 119–12210.1016/S0304-3940(99)00692-8
    1. Bernath S., Zigmond M. J. (1989). Dopamine may influence striatal GABA release via three separate mechanisms. Brain Res. 476, 373–37610.1016/0006-8993(89)91262-6
    1. Bevan M. D., Hallworth N. E., Baufreton J. (2007). GABAergic control of the subthalamic nucleus. Prog. Brain Res. 160, 173–188
    1. Bevan M. D., Magill P. J., Terman D., Bolam J. P., Wilson C. J. (2002). Move to the rhythm: oscillations in the subthalamic nucleus-external globus pallidus network. Trends Neurosci. 25, 525–53110.1016/S0166-2236(02)02235-X
    1. Borden L. A. (1996). GABA transporter heterogeneity: pharmacology and cellular localization. Neurochem. Int. 29, 335–35610.1016/0197-0186(95)00158-1
    1. Borden L. A., Smith K. E., Hartig P. R., Branchek T. A., Weinshank R. L. (1992). Molecular heterogeneity of the γ-aminobutyric acid (GABA) transport system. J. Biol. Chem. 267, 21098–21104
    1. Bracci E., Panzeri S. (2006). Excitatory GABAergic effects in striatal projection neurons. J. Neurophysiol. 95, 1285–129010.1152/jn.00598.2005
    1. Bragina L., Marchionni I., Omrani A., Cozzi A., Pellegrini-Giampietro D. E., Cherubini E., Conti F. (2008). GAT-1 regulates both tonic and phasic GABAA receptor-mediated inhibition in the cerebral cortex. J. Neurochem. 105, 1781–179310.1111/j.1471-4159.2008.05273.x
    1. Brecha N. C., Weigmann C. (1994). Expression of GAT-1, a high-affinity gamma-aminobutyric acid plasma membrane transporter in the rat retina. J. Comp. Neurol. 345, 602–61110.1002/cne.903450410
    1. Brotchie J. M. (2003). CB1 cannabinoid receptor signalling in Parkinson's disease. Curr. Opin. Pharmacol. 3, 54–6110.1016/S1471-4892(02)00011-5
    1. Chase T. N., Bibbiani F., Bara-Jimenez W., Dimitrova T., Oh-Lee J. D. (2003). Translating A2A antagonist KW6002 from animal models to Parkinsonian patients. Neurology 61, S107–S111
    1. Chen L., Yung W. H. (2003). Effects of the GABA-uptake inhibitor tiagabine in rat globus pallidus. Exp. Brain Res. 152, 263–26910.1007/s00221-003-1549-7
    1. Chiu C. S., Brickley S., Jensen K., Sputhwell A., Mckinney S., Candy S. C., Mody I., Laster H. A. (2005). GABA transporter deficiency causes tremor, ataxia, nervousness, and increased GABA induced tonic conductance in cerellum. J. Neurosci. 25, 3234–324510.1523/JNEUROSCI.3364-04.2005
    1. Clark J. A., Deutch A. Y., Gallipoli P. Z., Amara S. G. (1992). Functional expression and CAN distribution of a β-alanine-sensitive neuronal GABA transporter. Neuron 9, 337–34810.1016/0896-6273(92)90078-R
    1. Conti F., Melone M., De Biasi S., Minelli A., Brecha N. C., Ducati A. (1998). Neuronal and glial localization of GAT-1, a high-affinity gamma-aminobutyric acid plasma membrane transporter, in human cerebral cortex: with a note on its distribution in monkey cortex. J. Comp. Neurol. 396, 51–6310.1002/(SICI)1096-9861(19980622)396:1<51::AID-CNE5>;2-H
    1. Conti F., Minelli A., Melone M. (2004). GABA transporters in the mammalian cerebral cortex: localization, development and pathological implications. Brain Res. Rev. 45, 196–21210.1016/j.brainresrev.2004.03.003
    1. Conti F., Zuccarello L. V., Barbaresi P., Minelli A., Breacha N. C., Molone M. (1999). Neuronal, glial, and epithelial localization of gamma-aminobutric acid transporter 2, a high-affinity gamma-aminobutyric acid plasma membrane transporter, in the cerebral cortex and neighboring structures. J. Comp. Neurol. 409, 482–49410.1002/(SICI)1096-9861(19990705)409:3<482::AID-CNE11>;2-F
    1. Dalby N. O. (2000). GABA-level increasing and anticonvulsant effects of three different GABA uptake inhibitors. Neuropharmacology 39, 2399–240710.1016/S0028-3908(00)00075-7
    1. Dalby N. O. (2003). Inhibition of gamma-aminobutyric acid uptake: anatomy, physiology and effects against epileptic seizures. Eur. J. Pharmacol. 479, 127–13710.1016/j.ejphar.2003.08.063
    1. Del Arco A., Castaneda T. R., Mora F. (1998). Amphetamine releases GABA in the striatum of the freely moving rat: involvement of calcium and high affinity transporter mechanisms. Neuropharmacology 37, 199–20510.1016/S0028-3908(98)00013-6
    1. DeLong M. R. (1990). Primate models of movement disorders of basal ganglia origin. Trends Neurosci. 13, 281–28510.1016/0166-2236(90)90110-V
    1. Draguhn A., Heinemann U. (1996). Different mechanisms regulate IPSC kinetics in early postnatal and juvenile hippocampal granule cells. J. Neurophysiol. 76, 3983–3993
    1. Durkin M. M., Smith K. E., Borden L. A., Weinshank R. L., Branchek T. A., Gustafson E. L. (1995). Localization of messenger RNAs encoding three GABA transporters in rat brain: an in situ hybridization study. Brain Res. Mol. Brain Res. 33, 7–2110.1016/0169-328X(95)00101-W
    1. Engel D., Schmitz D., Gloveli T., Frahm C., Heinemann U., Draguhn A. (1998). Laminar difference in GABA uptake and GAT-1 expression in rat CA1. J. Physiol. 512, 643–64910.1111/j.1469-7793.1998.643bd.x
    1. Eulenburg V., Gomeza J. (2010). Neurotransmitter transporters expressed in glial cells as regulators of synapse function. Brain Res. Rev. 63, 103–11210.1016/j.brainresrev.2010.01.003
    1. Ficková M., Dahmen N., Fehr C., Hiemke C. (1999). Quantitation of GABA transporter 3 (GAT3) mRNA in rat brain by competitive RT-PCR. Brain Res. Protoc. 4, 341–35010.1016/S1385-299X(99)00039-2
    1. Fink-Jensen A., Suzdak P. D., Swedberg M. D. B., Judge M. E., Hansen L., Nielsen P. G. (1992). The γ-amonobutyric acid (GABA) uptake inhibitor, tiagabine, increases extracellular brain levels of GABA in awake rats. Eur. J. Pharmacol. 220, 197–20110.1016/0014-2999(92)90748-S
    1. Gadea A., Lopez-Colome A. M. (2001). Glial transporters for glutamate, glycine, and GABA: GABA transporters. J. Neurosci. Res. 63, 461–46810.1002/jnr.1040
    1. Galvan A., Hu X., Smith Y., Wichmann T. (2010). Localization and function of GABA transporters in the globus pallidus of Parkinsonian monkeys. Exp. Neurol. 223, 505–51510.1016/j.expneurol.2010.01.018
    1. Galvan A., Kuwajima M., Smith Y. (2006). Glutamate and GABA receptors and transporters in the basal ganglia: what does their subsynaptic localization reveal about their function? Neuroscience 143, 351–37510.1016/j.neuroscience.2006.09.019
    1. Galvan A., Villalba R. M., West S. M., Maidment N. T., Ackerson L. C., Smith Y., Wichmann T. (2005). GABAergic modulation of the activity of globus pallidus neurons in primates: in vivo analysis of the functions of GABA receptors and GABA transporters. J. Neurophysiol. 94, 990–100010.1152/jn.00068.2005
    1. Galvan A., Wichmann T. (2007). GABAergic circuits in the basal ganglia and movement disorders. Prog. Brain Res. 160, 287–312
    1. Gong N., Li Y., Cai G. Q., Niu R. F., Fang Q., Wu K., Chen Z., Lin L. N., Xu L., Fei J., Xu T. L. (2009). GABA transporter-1 activity modulates hippocampal theta oscillation and theta burst stimulation-induced long-term potentiation. J. Neurosci. 29, 15836–1584510.1523/JNEUROSCI.4643-09.2009
    1. Gonzalez B., Paz F., Floran L., Aceves J., Erlij D., Floran B. (2006). Adenosine A2A receptor stimulation decrease GAT-1-mediated GABA uptake in the globus pallidus of the rat. Neuropharmacology 51, 154–15910.1016/j.neuropharm.2006.03.011
    1. Gonzalez-Burgos G., Rotaru D. C., Zaitsev A. V., Povysheva N. V., Lewis D. A. (2009). GABA transporter GAT1 prevents spillover at proximal and distal GABA synapses onto primate preforontal cortex neuron. J. Neurophysiol. 101, 533–54710.1152/jn.91161.2008
    1. Guastella J., Nelson N., Nelson H., Czyzyk L., Keynan S., Miedel M. C., Davidson N., Lester H. A., Kanner B. I. (1990). Cloning and expression of a rat brain GABA transporter. Science 249, 1303–130610.1126/science.1975955
    1. Ikegaki N., Saito N., Hashima M., Tanaka C. (1994). Production of specific antibodies against GABA transporter subtypes (GAT1, GAT2, GAT3) and their application to immunocytochemistry. Mol. Brain Res. 26, 47–5410.1016/0169-328X(94)90072-8
    1. Isaacson J. S., Solis J. M., Nicoll R. A. (1993). Local and diffuse synaptic actions of GABA in the hippocampus. Neuron 10, 165–17510.1016/0896-6273(93)90308-E
    1. Itouji A., Sakai N., Tanaka C., Saito N. (1996). Neuronal and glial localization of two GABA transporters (GAT1 and GAT3) in the rat cerebellum. Mol. Brain Res. 37, 309–31610.1016/0169-328X(95)00342-P
    1. Jensen K., Chiu C. S., Sokolova I., Lester H. A., Mody I. (2003). GABA transporter-1 (GAT-1)-deficient mice: differential tonic activation of GABAA versus GABAB receptors in the hippocampus. J. Neurophysiol. 90, 2690–270110.1152/jn.00240.2003
    1. Jin X.-T., Fare J.-F., Smith Y. (2011). Differential localization and functions of GABA transporters, GAT-1 and GAT-3, in the rat globus pallidus. Eur. J. Neurosci. 33, 1504–151810.1111/j.1460-9568.2011.07636.x
    1. Jin X.-T., Pare J.-F., Smith Y. (2009). “Blockade of GABA transporter (GAT-1) modulates the GABAergic transmission in the rat globus pallidus,” in Basal Ganglia IX, eds Groenewegen H. J., Berendse H. J., Voorn P. J. (New York: Springer Press; ), 297–307
    1. Jin X.-T., Smith Y. (2009). GABA transporters modulate glutamatergic transmission in the rat globus pallidus. Soc. Neurosci. Abstr. 134.18.
    1. Jursky F., Nelson N. (1996). Developmental expression of GABA transporters GAT1 and GAT4 suggests involvement in brain maturation. J. Neurochem. 67, 857–86710.1046/j.1471-4159.1996.67020857.x
    1. Kanda T., Jackson M. J., Smith L. A., Pearce R. K., Nakamura J., Kase H., Kuwana Y., Jenner P. (2000). Combined use of the adenosine A(2A) antagonist KW-6002 with L-DOPA or with selective D1 or D2 dopamine agonist increases antiparkinsonian activity but not dyskinesia in MPTP-treated monkeys. Exp. Neurol. 162, 321–32710.1006/exnr.2000.7350
    1. Karakossian M. H., Spencer S. R., Gomez A. Q., Padilla O. R., Sacher A., Loo D. D., Nelson N., Eskandari S. (2005). Novel properties of a mouse gamma-aminobutyric acid transporter (GAT4). J. Membr. Biol. 203, 65–8210.1007/s00232-004-0732-5
    1. Kawaguchi Y., Wilson C. J., Emson P. C. (1990). Projection subtypes of rat neostriatal matrix cells revealed by intracellular injection of biocytin. J. Neurosci. 10, 3421–3438
    1. Keros S., Hablitz J. J. (2005). Subtype-specific GABA transporter antagonists synergistically modulate phasic and tonic GABAA conductances in rat neocortex. J. Neurophysiol. 94, 2073–208510.1152/jn.00520.2005
    1. Kinney G. A. (2005). GAT-3 transporters regulate inhibition in the neocortex. J. Neurophysiol. 94, 4533–453710.1152/jn.00420.2005
    1. Kirmse K., Dvorzhak A., Kirischuk S., Grantyn R. (2008). GABA transporter 1 tunes GABAergic synaptic transmission at output neurons of the mouse neostriatum. J. Physiol. 586, 5665–567810.1113/jphysiol.2008.161943
    1. Kirmse K., Kirischuk S., Grantyn R. (2009). Role of GABA transporter 3 in GABAergic synaptic transmission at striatal output neurons. Synapse 63, 921–92910.1002/syn.20675
    1. Lewitt P. A., Rezai A. R., Leehey M. A., Ojemann S. G., Flaherty A. W., Eskandar E. N., Kostyk S. K., Thomas K., Sarkar A., Siddigui M. S., Tatter S. B., Schwalb J. M., Poston K. L., Henderson J. M., Kurlan R. M., Richard I. H., Van Meter L., Sapan C. V., During M. J., Kaplitt M. G., Feigin A. (2011). AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial. Lancet Neurol. 10, 309–31910.1016/S1474-4422(11)70039-4
    1. Lindsly C., Fraxier C. (2010). Two distinct and activity-dependent mechanisms contribute to autoreceptor-mediated inhibition of GABAergic afferents to hilar mossy cells. J. Physiol. 588, 2801–282210.1113/jphysiol.2009.184648
    1. Liu Q.-R., Lopez-Crcuera B., Mandiyan S., Nelson H., Nelson N. (1993). Molecular characterization of four pharmacologically distinct y-aminobutyric acid transporters in mouse brain. J. Biol. Chem. 268, 2106–2112
    1. Loo D. D., Eskandari S., Boorer K. J., Sarkar H. K., Wright E. M. (2000). Role of Cl in electrogenic Na-coupled cotransporters GAT1 and SGLT1. J. Biol. Chem. 275, 37414–3742210.1074/jbc.C000222200
    1. Minelli A., Barbaresi P., Conti F. (2003). Postnatal development of high-affinity plasma membrane transporters GAT-2 and GAT-3 in the rat cerebral cortex. Dev. Brain Res. 142, 7–1810.1016/S0165-3806(03)00007-5
    1. Minelli A., Brecha N. C., Karschin C., DeBiasi S., Conti F. (1995). GAT1, a high-affinity GABA plasma membrane transporter, is localized to neurons and astroglia in the cerebral cortex. J. Neurosci. 15, 7734–7746
    1. Minelli A., DeBiasi S., Brecha N. C., Vitellaro Zuccarello L., Conti F. (1996). GAT-3, a high-affinity GABA plasma membrane transporter, is localized to localized to astrocytic processes, and it is not confined to the vicinty of GABAergic synapses in the cerebral cortex. J. Neurosci. 16, 6255–6264
    1. Nelson H., Mandiyan S., Nelson N. (1990). Cloning of the human brain GABA transporter. FEBS Lett. 269, 181–18410.1016/0014-5793(90)81149-I
    1. Ng C. H., Wang X. S., Ong W. Y. (2000). A light and electron microscopic study of the GABA transporter GAT-3 in the monkey basal ganglia and brainstem. J. Neurocytol. 29, 595–60310.1023/A:1011076219493
    1. Nishimura M., Sato K., Mizuno M., Yoshiya I., Shimada S., Saito N., Tohyama M. (1997). Differential expression patterns of GABA transporters (GAT1-3) in the rat olfactory bulb. Mol. Brain Res. 45, 268–27410.1016/S0169-328X(96)00259-8
    1. Nusser Z., Mody I. (2002). Selective modulation of tonic and phasic inhibitions in dentate gyrus granule cells. J. Neurophysiol. 87, 2624–2628
    1. Overstreet L. S., Jones M. V., Westbrook G. L. (2000). Slow desensitization regulates the availability of synaptic GABA(A) receptors. J. Neurosci. 20, 7914–7921
    1. Overstreet L. S., Westbrook G. L. (2003). Synaptic density regulates independence at unitary inhibitory synapses. J. Neurosci. 23, 2618–2626
    1. Plenz D., Kitai S. T. (1999). A basal ganglia pacemaker formed by the subthalamic nucleus and external globus pallidus. Nature 400, 677–68210.1038/23281
    1. Pow D. V., Sullivan R. K. P., Willliams S. M., Scott H. L., Dodd P. R., Finkelstein D. (2005). Differential expression of the GABA transporters GAT-1 and GAT-3 in brains of rats, cats, monkeys and humans. Cell Tissue. Res. 320, 379–39210.1007/s00441-004-0928-0
    1. Radian R., Ottersen O. P., Storm-Mathisen J., Castel M., Kanner B. I. (1990). Immunocytochemical localization of the GABA transporter in rat brain. J. Neurosci. 10, 1319–1330
    1. Rattray M., Priestley J. V. (1993). Differential expression of GABA transporter-1 messenger RNA in subpopulations of GABA neurones. Neurosci. Lett. 156, 163–16510.1016/0304-3940(93)90463-U
    1. Ribak C. E., Tong W. M., Brecha N. C. (1996). GABA plasma membrane transporters, GAT-1 and GAT-3, display different distributions in the rat hippocampus. J. Comp. Neurol. 367, 595–60610.1002/(SICI)1096-9861(19960415)367:4<595::AID-CNE9>;2-#
    1. Richards D. A., Bowery N. C. (1996). Comparative effects of the GABA uptake inhibitors, tiagabine and NNC-711, on extracellular GABA levels in the rat ventrolateral thalamus. Neurochem. Res. 21, 135–14010.1007/BF02529130
    1. Richerson G. B., Wu Y. (2003). Dynamic equilibrium of neurotransmitter transporters: not just for reuptake anymore. J. Neurophysiol. 90, 1363–137410.1152/jn.00317.2003
    1. Roepstorff A., Lambert J. D. (1992). Comparison of the effect of the GABA uptake blockers, tiagabine and nipecotic acid, on inhibitory synaptic efficacy in hippocampal CA1 neurons. Neurosci. Lett. 146, 131–13410.1016/0304-3940(92)90060-K
    1. Roepstorff A., Lambert J. D. (1994). Factors contribution to the decay of the stimulus-evoked IPSC in rat hippocampal CA1 neurons. J. Neurophysiol. 72, 2911–2926
    1. Romero J., Lastres-Becker I., de Miguel R., Berrendero F., Ramos J. A., Fernandez-Ruiz J. (2002). The endogenous cannabinoid system and the basal ganglia. Biochemical, pharmacological, and therapeutic aspects. Pharmacol. Ther. 95, 137–15210.1016/S0163-7258(02)00253-X
    1. Rossi D. L., Hammann M., Attwell D. (2003). Multiple modes of GABAergic inhibition of rat cerebellar cells. J. Physiol. 548, 97–11010.1113/jphysiol.2002.036459
    1. Sacher A., Nelson N., Ogi J. T., Wright E. M., Loo D. D., Eskandari S. (2002). Prestead-state and steady-state kinetics and turnover rate of the mouse gamma-aminobutyric acid transporter (mGAT3) J. Membr. Biol. 190, 57–7310.1007/s00232-002-1024-6
    1. Safiulina V. F., Cherubini E. (2009). At immature mossy fibers-CA3 connection, activation of presynaptic GABAB receptors bt endogenously released GABA contributes to synapses silencing. Front. Cell. Neurosci. 3:1.10.3389/neuro.03.001.2009
    1. Sarup A., Larsson O. M., Schousboe A. (2003). GABA transporters and GABA-transaminase as drug targets. Curr. Drug Targets CNS Neurol. Disord. 2, 369–27710.2174/1568007033482788
    1. Schoffelmeer A. N. M., Vanderschuren L. J. M. J., Vries T. J. De., Hogenboom F., Wardeh G., Mulder A. H. (2000). Synergistically interacting dopamine D1 and NMDA receptors mediate nonvesicular transporter-dependent GABA release from rat striatal medium spiny neurons. J. Neurosci. 20, 3496–3505
    1. Schwartz T. L., Nihalani N. (2006). Tiagabine in anxiety disorders. Expert Opin. Pharmacother. 7, 1977–198710.1517/14656566.7.6.803
    1. Scimemi A., Semyanov A., Sperk G., Kullmann D. M., Walker M. C. (2005). Multiple and plastic receptors mediate tonic GABAA receptor currents in the hippocampus. J. Neurosci. 25, 10016–1002410.1523/JNEUROSCI.2520-05.2005
    1. Semyanov A., Walker M. C., Kullmann D. M. (2003). GABA uptake regulates cortical excitability via cell type-specific tonic inhibition. Nat. Neurosci. 6, 484–490
    1. Semyanov A., Walker M. C., Kullmann D. M., Silver R. A. (2004). Tonically active GABAA receptor: modulating gain and maintaining the tone. Trends Neurosci. 27, 262–26910.1016/j.tins.2004.03.005
    1. Sipilä S. T., Voipio J., Kaila K. (2007). GAT-1 acts to limit a tonic GABAA current in rat CA3 pyramidal neurons at birth. Eur. J. Neurosci. 25, 771–722
    1. Swan M., Najelahim A., Watson R. E. B., Benett J. P. (1994). Distribution of mRNA for the GABA transporter GAT-1 in the rat brain: evidence that GABA uptake is not limited to presynaptic neurons. J. Anat. 185, 315–323
    1. Thompson S. M., Gähwiler B. H. (1992). Effects of the GABA uptake inhibitor tiagabine on inhibitory synaptic potentials in rat hippocampal slice cultures. J. Neurophysiol. 67, 1698–1701
    1. Venderova K., Brown T. M., Brotchie J. M. (2005). Differential effects of endocannabinoids on [3H]-GABA uptake in the rat globus pallidus. Exp. Neuro. 194, 284–28710.1016/j.expneurol.2005.02.012
    1. Waldmeier P. C., Stocklin K., Feldtrauer J. J. (1992). Weak effects of local and systemic adaministration of the GABA uptake inhibitor, SKF 89976A, on extracellular GABA in the rat striatum. Naunyn Schmiedebergs Arch. Exp. Pathol. Pharmakol. 345, 544–547
    1. Wang X. S., Ong W. Y. (1999). A light and electron microscopic study of GAT-1 in the monkey basal ganglia. J. Neurocytol. 28, 1053–106110.1023/A:1007056608820
    1. Wu Y., Wang W., Diez-Sampedro A., Richerson G. B. (2007). Nonvesicular inhibitory neurotransmission via reversal of the GABA transporter GAT-1. Neuron 56, 851–86510.1016/j.neuron.2007.10.021
    1. Yamauchi A., Uchida S., Kwon H. M., Preston A. S., Robey R. B., Garcia-Perez A., Burg M. B., Handler J. S. (1992). Cloning of a Na (+)-and Cl(-)-dependent betaine transporter that is regulated by hypertonicity. J. Biol. Chem. 267, 649–652
    1. Yasumi M., Sato K., Shimada S., Nishimura M., Tohyama M. (1997). Regional distribution of GABA transporter 1 (GAT1) mRNA in the rat brain: comparison with glutamic acid decarboxylase67 (GAD67) mRNA localization. Brain Res. Mol. Brain Res. 44, 205–21810.1016/S0169-328X(96)00200-8
    1. Zhou X. M., Ong W. Y. (2004). A light and electron microscopic study of betaine/GABA transporter distribution in the monkey cerebral neocortex and hippocampus. J. Neurocytol. 33, 233–24010.1023/B:NEUR.0000030698.66675.90

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