Skip to main content
SpringerLink
Log in

Glial GABA Transporters as Modulators of Inhibitory Signalling in Epilepsy and Stroke

  • Chapter
  • First Online:
Book cover Glial Amino Acid Transporters

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 16))

Abstract

Imbalances in GABA-mediated tonic inhibition are involved in several pathophysiological conditions. A classical way of controlling tonic inhibition is through pharmacological intervention with extrasynaptic GABAA receptors that sense ambient GABA and mediate a persistent GABAergic conductance. An increase in tonic inhibition may, however, also be obtained indirectly by inhibiting glial GABA transporters (GATs). These are sodium-coupled membrane transport proteins that normally act to terminate GABA neurotransmitter action by taking up GABA into surrounding astrocytes. The aim of the review is to provide an overview of glial GATs in regulating tonic inhibition, especially in epilepsy and stroke. This entails a comprehensive summary of changes known to occur in GAT expression levels and signalling following epileptic and ischemic insults. Further, we discuss the accumulating pharmacological evidence for targeting GATs in these diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Akbar MT, Rattray M, Williams RJ, Chong NWS, Meldrum BS. Reduction of GABA and glutamate transporter messenger RNAs in the severe-seizure genetically epilepsy-prone rat. Neuroscience. 1998;85(4):1235–51.

    Article  CAS  PubMed  Google Scholar 

  • Al-Khawaja A, Petersen JG, Damgaard M, Jensen MH, Vogensen SB, Lie MEK, et al. Pharmacological identification of a guanidine-containing β-alanine analogue with low micromolar potency and selectivity for the betaine/GABA transporter 1 (BGT1). Neurochem Res. 2014;39(10):1988–96.

    Article  CAS  PubMed  Google Scholar 

  • Anderson M, Burda J, Ren Y, Ao Y, O’Shea T, Kawaguchi R, et al. Astrocyte scar formation aids central nervous system axon regeneration. Nature. 2016;532(7598):195–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • André V, Marescaux C, Nehlig A, Fritschy JM. Alterations of hippocampal GABAergic system contribute to development of spontaneous recurrent seizures in the rat lithium-pilocarpine model of temporal lobe epilepsy. Hippocampus. 2001;11(4):452–68.

    Article  PubMed  Google Scholar 

  • Arellano JI, Muñoz A, Ballesteros-Yáñez I, Sola RG, DeFelipe J. Histopathology and reorganization of chandelier cells in the human epileptic sclerotic hippocampus. Brain. 2004;127(1):45–64.

    Article  CAS  PubMed  Google Scholar 

  • Aronica E, Redeker S, Boer K, Spliet WGM, van Rijen PC, Gorter JA, et al. Inhibitory networks in epilepsy-associated gangliogliomas and in the perilesional epileptic cortex. Epilepsy Res. 2007;74(1):33–44.

    Article  CAS  PubMed  Google Scholar 

  • Atack J, Bayley P, Seabrook G, Wafford K, McKernan R, Dawson G. L-655,708 enhances cognition in rats but is not proconvulsant at a dose selective for α5-containing GABAA receptors. Neuropharmacology. 2006;51(6):1023–9.

    Article  CAS  PubMed  Google Scholar 

  • Baldwin HA, Williams JL, Snares M, Ferreira T, Cross AJ, Green AR. Attenuation by chlormethiazole administration of the rise in extracellular amino acids following focal ischaemia in the cerebral cortex of the rat. Br J Pharmacol. 1994 May;112(1):188–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Belelli D, Harrison NL, Maguire J, Macdonald RL, Walker MC, Cope DW. Extrasynaptic GABAA receptors: form, pharmacology, and function. J Neurosci. 2009;29(41):12757–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Berkovic SF, Mulley JC, Scheffer IE, Petrou S. Human epilepsies: interaction of genetic and acquired factors. Trends Neurosci. 2006;29(7):391–7.

    Article  CAS  PubMed  Google Scholar 

  • Bettler B, Kaupmann K, Mosbacher J, Gassmann M. Molecular structure and physiological functions of GABAB receptors. Physiol Rev. 2004;84(3):835–67.

    Article  CAS  PubMed  Google Scholar 

  • Bhattacharya P, Pandey AK, Paul S, Patnaik R. Alleviation of glutamate mediated neuronal insult by piroxicam in rodent model of focal cerebral ischemia: a possible mechanism of GABA agonism. J Physiol Biochem. 2014;70(4):901–13.

    Article  CAS  PubMed  Google Scholar 

  • Blicher JU, Near J, Næss-Schmidt E, Stagg CJ, Johansen-Berg H, Nielsen JF, et al. GABA levels are decreased after stroke and GABA changes during rehabilitation correlate with motor improvement. Neurorehabil Neural Repair. 2015;29(3):278–86.

    Article  PubMed  Google Scholar 

  • Bolvig T, Larsson OM, Pickering DS, Nelson N, Falch E, Krogsgaard-Larsen P, et al. Action of bicyclic isoxazole GABA analogues on GABA transporters and its relation to anticonvulsant activity. Eur J Pharmacol. 1999;375(1–3):367–74.

    Article  CAS  PubMed  Google Scholar 

  • Borden LA, Caplan MJ. GABA transporter heterogeneity: pharmacology and cellular localization. Neurochem Int. 1996;29(4):335–56.

    Article  CAS  PubMed  Google Scholar 

  • Borden LA, Smith KE, Gustafson EL, Branchek TA, Weinshank RL. Cloning and expression of a betaine/GABA transporter from human brain. J Neurochem. 1995;64(3):977–84.

    Article  CAS  PubMed  Google Scholar 

  • Bouilleret V, Loup F, Kiener T, Marescaux C, Fritschy JM. Early loss of interneurons and delayed subunit-specific changes in GABAA-receptor expression in a mouse model of mesial temporal lobe epilepsy. Hippocampus. 2000;10(3):305–24.

    Article  CAS  PubMed  Google Scholar 

  • Brickley SG, Mody I. Extrasynaptic GABAA receptors: their function in the CNS and implications for disease. Neuron. 2012;73(1):23–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brown CE, Aminoltejari K, Erb H, Winship IR, Murphy TH. In vivo voltage-sensitive dye imaging in adult mice reveals that somatosensory maps lost to stroke are replaced over weeks by new structural and functional circuits with prolonged modes of activation within both the peri-infarct zone and distant sites. J Neurosci. 2009;29(6):1719–34.

    Article  CAS  PubMed  Google Scholar 

  • Burda JE, Sofroniew MV. Reactive gliosis and the multicellular response to CNS damage and disease. Neuron. 2014;81(2):229–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Calcagnotto ME, Paredes MF, Baraban SC. Heterotopic neurons with altered inhibitory synaptic function in an animal model of malformation-associated epilepsy. J Neurosci. 2002;22(17):7596–605.

    CAS  PubMed  Google Scholar 

  • Calcagnotto ME, Paredes MF, Tihan T, Barbaro NM, Baraban SC. Dysfunction of synaptic inhibition in epilepsy associated with focal cortical dysplasia. J Neurosci. 2005;25(42):9649–57.

    Article  CAS  PubMed  Google Scholar 

  • Campbell AM, Holmes O. Bicuculline epileptogenesis in the rat. Brain Res. 1984;323(2):239–46.

    Article  CAS  PubMed  Google Scholar 

  • Carmichael ST. Brain excitability in stroke: the yin and yang of stroke progression. Arch Neurol. 2012;69(2):161–7.

    Article  PubMed  Google Scholar 

  • Chen F, Suzuki Y, Nagai N, Jin L, Yu J, Wang H, et al. Rodent stroke induced by photochemical occlusion of proximal middle cerebral artery: evolution monitored with MR imaging and histopathology. Eur J Radiol. 2007;63(1):68–75.

    Article  PubMed  Google Scholar 

  • Chen Xu W, Yi Y, Qiu L, Shuaib A. Neuroprotective activity of tiagabine in a focal embolic model of cerebral ischemia. Brain Res. 2000;874(1):75–7.

    Article  CAS  PubMed  Google Scholar 

  • Chiu C-S, Brickley S, Jensen K, Southwell A, Mckinney S, Cull-Candy S, et al. GABA transporter deficiency causes tremor, ataxia, nervousness, and increased GABA-induced tonic conductance in cerebellum. J Neurosci. 2005;25(12):3234–45.

    Article  CAS  PubMed  Google Scholar 

  • Clarkson AN. Perisynaptic GABA receptors the overzealous protector. Adv Pharmacol Sci. 2012;2012:708428.

    PubMed  PubMed Central  Google Scholar 

  • Clarkson AN, Huang BS, Macisaac SE, Mody I, Carmichael ST. Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. Nature. 2010;468(7321):305–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clausen RP, Moltzen EK, Perregaard J, Lenz SM, Sanchez C, Falch E, et al. Selective inhibitors of GABA uptake: synthesis and molecular pharmacology of 4-N-methylamino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol analogues. Bioorg Med Chem. 2005;13(3):895–908.

    Article  CAS  PubMed  Google Scholar 

  • Collinson N, Kuenzi FM, Jarolimek W, Maubach KA, Cothliff R, Sur C, et al. Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the α5 subunit of the GABAA receptor. J Neurosci. 2002;22(13):5572–80.

    CAS  PubMed  Google Scholar 

  • Conti F, Melone M, De Biasi S, Minelli A, Brecha NC, Ducati A. Neuronal and glial localization of GAT-1, a high-affinity γ-aminobutyric acid plasma membrane transporter, in human cerebral cortex: with a note on its distribution in monkey cortex. J Comp Neurol. 1998;396(1):51–63.

    Article  CAS  PubMed  Google Scholar 

  • Conti F, Minelli A, Melone M. GABA transporters in the mammalian cerebral cortex: localization, development and pathological implications. Brain Res Rev. 2004;45(3):196–212.

    Article  CAS  PubMed  Google Scholar 

  • Conti F, Zuccarello LV, Barbaresi P, Minelli A, Brecha NC, Melone M. Neuronal, glial, and epithelial localization of gamma-aminobutyric acid transporter 2, a high-affinity gamma-aminobutyric acid plasma membrane transporter, in the cerebral cortex and neighboring structures. J Comp Neurol. 1999;409(3):482–94.

    Article  CAS  PubMed  Google Scholar 

  • Cope DW, Di Giovanni G, Fyson SJ, Orbán G, Errington AC, Lörincz ML, et al. Enhanced tonic GABAA inhibition in typical absence epilepsy. Nat Med. 2009;15(12):1392–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Costa C, Leone G, Saulle E, Pisani F, Bernardi G, Calabresi P. Coactivation of GABAA and GABAB receptor results in neuroprotection during in vitro ischemia. Stroke. 2004;35(2):596–600.

    Article  CAS  PubMed  Google Scholar 

  • Curtis DR, Duggan AW, Felix D, Johnston G. GABA, bicuculline and central inhibition. Nature. 1970;226(5252):1222–4.

    Article  CAS  PubMed  Google Scholar 

  • Dalby NO. GABA-level increasing and anticonvulsant effects of three different GABA uptake inhibitors. Neuropharmacology. 2000;39(12):2399–407.

    Article  CAS  PubMed  Google Scholar 

  • Dalby NO. Inhibition of γ-aminobutyric acid uptake: anatomy, physiology and effects against epileptic seizures. Eur J Pharmacol. 2003;479(1–3):127–37.

    Article  CAS  PubMed  Google Scholar 

  • Dalby NO, Thomsen C, Fink-Jensen A, Lundbeck J, Søkilde B, Man CM, et al. Anticonvulsant properties of two GABA uptake inhibitors NNC 05-2045 and NNC 05-2090, not acting preferentially on GAT-1. Epilepsy Res. 1997;28(1):51–61.

    Article  CAS  PubMed  Google Scholar 

  • Damgaard M, Haugaard AS, Al-Khawaja A, Lie MEK, Wellendorph P, Clausen RP, et al. Development of non-GAT1 selective GABA uptake inhibitors. In: Ortega A, Schousboe A, editors. Glial amino acid transporters. Cham: Springer; in press.

    Google Scholar 

  • Damgaard M, Al-Khawaja A, Vogensen SB, Jurik A, Sijm M, Lie MEK, et al. Identification of the first highly subtype-selective inhibitor of human GABA transporter GAT3. ACS Chem Neurosci. 2015;6(9):1591–9.

    Article  CAS  PubMed  Google Scholar 

  • Das N, Dhanawat M, Shrivastava SK. An overview on antiepileptic drugs. Drug Discov Ther. 2012;6(4):178–93.

    CAS  PubMed  Google Scholar 

  • Dhar TGM, Borden LA, Tyagarajan S, Smith KE, Branchek TA, Weinshank RL, et al. Design, synthesis and evaluation of substituted triarylnipecotic acid derivatives as GABA uptake inhibitors: identification of a ligand with moderate affinity and selectivity for the cloned human GABA transporter GAT- 3. J Med Chem. 1994;37(15):2334–42.

    Article  CAS  PubMed  Google Scholar 

  • Dobkin BH. Training and exercise to drive poststroke recovery. Nat Clin Pract Neurol. 2008;4(2):76–85.

    Article  PubMed  PubMed Central  Google Scholar 

  • Dobkin BH, Dorsch A. New evidence for therapies in stroke rehabilitation. Curr Atheroscler Rep. 2013;15(6):331.

    Article  PubMed  PubMed Central  Google Scholar 

  • Doi T, Ueda Y, Nagatomo K, Willmore LJ. Role of glutamate and GABA transporters in development of pentylenetetrazol-kindling. Neurochem Res. 2009;34(7):1324–31.

    Article  CAS  PubMed  Google Scholar 

  • Doi T, Ueda Y, Tokumaru J, Willmore LJ. Molecular regulation of glutamate and GABA transporter proteins by clobazam during epileptogenesis in Fe+++-induced epileptic rats. Mol Brain Res. 2005;142(2):91–6.

    Article  CAS  PubMed  Google Scholar 

  • Doyle KP, Simon RP, Stenzel-Poore MP. Mechanisms of ischemic brain damage. Neuropharmacology. 2008 Sep;55(3):310–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • During MJ, Ryder KM, Spencer DD. Hippocampal GABA transporter function in temporal-lobe epilepsy. Nature. 1995;376(6536):174–7.

    Article  CAS  PubMed  Google Scholar 

  • Emberson J, Lees K, Lyden P, Blackwell L, Albers G, Bluhmki E, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet. 2014;385(9958):1929–35.

    Article  CAS  Google Scholar 

  • Engelborghs S, D’Hooge R, De Deyn PP. Pathophysiology of epilepsy. Acta Neurol Belg. 2000;100(4):201–13.

    CAS  PubMed  Google Scholar 

  • Errington AC, Cope DW, Crunelli V. Augmentation of tonic GABAA inhibition in absence epilepsy: therapeutic value of inverse agonists at extrasynaptic GABAA receptors. Adv Pharmacol Sci. 2011;2011:1–12.

    Article  CAS  Google Scholar 

  • Esclapez M, Houser CR. Up-regulation of GAD65 and GAD67 in remaining hippocampal GABA neurons in a model of temporal lobe epilepsy. J Comp Neurol. 1999;412(3):488–505.

    Article  CAS  PubMed  Google Scholar 

  • Farrant M, Nusser Z. Variations on an inhibitory theme: phasic and tonic activation of GABAA receptors. Nat Rev Neurosci. 2005;6(3):215–29.

    Article  CAS  PubMed  Google Scholar 

  • Fink-Jensen A, Suzdak PD, Swedberg MDB, Judge ME, Hansen L, Nielsen PG. The γ-aminobutyric acid (GABA) uptake inhibitor, tiagabine, increases extracellular brain levels of GABA in awake rats. Eur J Pharmacol. 1992;220(2–3):197–201.

    Article  CAS  PubMed  Google Scholar 

  • Frahm C, Haupt C, Weinandy F, Siegel G, Bruehl C, Witte OW. Regulation of GABA transporter mRNA and protein after photothrombotic infarct in rat brain. J Comp Neurol. 2004;478(2):176–88.

    Article  CAS  PubMed  Google Scholar 

  • Freichel C, Potschka H, Ebert U, Brandt C, Löscher W. Acute changes in the neuronal expression of GABA and glutamate decarboxylase isoforms in the rat piriform cortex following status epilepticus. Neuroscience. 2006;141(4):2177–94.

    Article  CAS  PubMed  Google Scholar 

  • Fu CY, He XY, Li XF, Zhang X, Huang ZW, Li J, et al. Nefiracetam attenuates pro-inflammatory cytokines and GABA transporter in specific brain regions of rats with post-ischemic seizures. Cell Physiol Biochem. 2015;37(5):2023–31.

    Article  CAS  PubMed  Google Scholar 

  • Gastaut H, Naquet R, Poire R, Tassinari C. Treatment of status epilepticus with diazepam (Valium). Epilepsia. 1965;6:167–82.

    Article  CAS  PubMed  Google Scholar 

  • Ginsberg MD. Neuroprotection for ischemic stroke: past, present and future. Neuropharmacology. 2008;55(3):363–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gonsalves SF, Twitchell B, Harbaugh RE, Krogsgaard-Larsen P, Schousboe A. Anticonvulsant activity of the glial GABA uptake inhibitor, THAO, in chemical seizures. Eur J Pharmacol. 1989;168(2):265–8.

    Article  CAS  PubMed  Google Scholar 

  • Green AR, Hainsworth AH, Jackson DM. GABA potentiation: a logical pharmacological approach for the treatment of acute ischaemic stroke. Neuropharmacology. 2000;39(9):1483–94.

    Article  CAS  PubMed  Google Scholar 

  • Héja L, Barabas P, Nyitrai G, Kekesi KA, Lasztoczi B, Toke O, et al. Glutamate uptake triggers transporter-mediated GABA release from astrocytes. PLoS One. 2009;4(9):e7153.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Héja L, Nyitrai G, Kékesi O, Dobolyi Á, Szabó P, Fiáth R, et al. Astrocytes convert network excitation to tonic inhibition of neurons. BMC Biol. 2012;10(26):1–22.

    Google Scholar 

  • Hernandez TD, Schallert T. Seizures and recovery from experimental brain damage. Exp Neurol. 1988;102(3):318–24.

    Article  CAS  PubMed  Google Scholar 

  • Hernandez-Rabaza V, Cabrera-Pastor A, Taoro-Gonzalez L, Gonzalez-Usano A, Agusti A, Balzano T, et al. Neuroinflammation increases GABAergic tone and impairs cognitive and motor function in hyperammonemia by increasing GAT-3 membrane expression. Reversal by sulforaphane by promoting M2 polarization of microglia. J Neuroinflammation. 2016;13(1):83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hill RG, Simmonds MA, Straughan DW. A comparative study of some convulsant substances as γ-aminobutyric acid antagonists in the feline cerebral cortex. Br J Pharmacol. 1973;49(1):37–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hines RM, Davies PA, Moss SJ, Maguire J. Functional regulation of GABAA receptors in nervous system pathologies. Curr Opin Neurobiol. 2012;22(3):552–8.

    Article  CAS  PubMed  Google Scholar 

  • Hirao T, Morimoto K, Yamamoto Y, Watanabe T, Sato H, Sato K, et al. Time-dependent and regional expression of GABA transporter mRNAs following amygdala-kindled seizures in rats. Mol Brain Res. 1998;54(1):49–55.

    Article  CAS  PubMed  Google Scholar 

  • Hirose S, Mitsudome A, Okada M, Kaneko S. Genetics of idiopathic epilepsies. Epilepsia. 2005;46(Suppl. 1):38–43.

    Article  CAS  PubMed  Google Scholar 

  • Hutchinson PJ, O’Connell MT, Al-Rawi PG, Kett-White CR, Gupta AK, Maskell LB, et al. Increases in GABA concentrations during cerebral ischaemia: a microdialysis study of extracellular amino acids. J Neurol Neurosurg Psychiatry. 2002;72(1):99–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Høg S, Greenwood JR, Madsen KB, Larsson OM, Frølund B, Schousboe A, et al. Structure-activity relationships of selective GABA uptake inhibitors. Curr Top Med Chem. 2006;6(17):1861–82.

    Article  PubMed  Google Scholar 

  • Inglefield JR, Perry JM, Schwartz RD. Postischemic inhibition of GABA reuptake by tiagabine slows neuronal death in the gerbil hippocampus. Hippocampus. 1995;5(5):460–8.

    Article  CAS  PubMed  Google Scholar 

  • Iqbal S, Baziany A, Gordon S, Wright S, Hussain M, Miyashita H, et al. Neuroprotective effect of tiagabine in transient forebrain global ischemia: an in vivo microdialysis, behavioral, and histological study. Brain Res. 2002;946(2):162–70.

    Article  CAS  PubMed  Google Scholar 

  • Jaenisch N, Liebmann L, Guenther M, Hübner CA, Frahm C, Witte OW. Reduced tonic inhibition after stroke promotes motor performance and epileptic seizures. Sci Report. 2016;6:26173.

    Article  CAS  Google Scholar 

  • Jardetzky O. Simple allosteric model for membrane pumps. Nature. 1966;211(5052):969–70.

    Article  CAS  PubMed  Google Scholar 

  • Jensen K, Chiu CS, Sokolova I, Lester HA, Mody I. GABA transporter-1 (GAT1)-deficient mice: differential tonic activation of GABAA versus GABAB receptors in the hippocampus. J Neurophysiol. 2003;90(4):2690–701.

    Article  CAS  PubMed  Google Scholar 

  • Johansen FF, Diemer NH. Enhancement of GABA neurotransmission after cerebral ischemia in the rat reduces loss of hippocampal CA1 pyramidal cells. Acta Neurol Scand. 1991;84(1):1–6.

    Article  CAS  PubMed  Google Scholar 

  • Juhász G, Kékesi KA, Nyitrai G, Dobolyi A, Krogsgaard-Larsen P, Schousboe A. Differential effects of nipecotic acid and 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol on extracellular α-aminobutyrate levels in rat thalamus. Eur J Pharmacol. 1997;331(2–3):139–44.

    Article  PubMed  Google Scholar 

  • Kaim S, Rosenstein I. Anticonvulsant properties of a new psychotherapeutic drug. Dis Nerv Syst. 1960;21(3):46–8.

    PubMed  Google Scholar 

  • Kang TC, Kim HS, Seo MO, Park SK, Kwon HY, Kang JH, et al. The changes in the expressions of γ-aminobutyric acid transporters in the gerbil hippocampal complex following spontaneous seizure. Neurosci Lett. 2001;310(1):29–32.

    Article  CAS  PubMed  Google Scholar 

  • Kanthan R, Shuaib A, Griebel R, Miyashita H. Intracerebral human microdialysis. In vivo study of an acute focal ischemic model of the human brain. Stroke. 1995;26(5):870–3.

    Article  CAS  PubMed  Google Scholar 

  • Keros S, Hablitz JJ. Subtype-specific GABA transporter antagonists synergistically modulate phasic and tonic GABAA conductances in rat neocortex. J Neurophysiol. 2005;94(3):2073–85.

    Article  CAS  PubMed  Google Scholar 

  • Kersanté F, Rowley SCS, Pavlov I, Gutièrrez-Mecinas M, Semyanov A, Reul JMHM, et al. A functional role for both γ-aminobutyric acid (GABA) transporter-1 and GABA transporter-3 in the modulation of extracellular GABA and GABAergic tonic conductances in the rat hippocampus. J Physiol. 2013;591(10):2429–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kett-White R, O’Connell MT, Hutchinson PJA, Al-Rawi PG, Gupta AK, Pickard JD, et al. Extracellular amino acid changes in patients during reversible cerebral ischaemia. Acta Neurochir Suppl. 2005;95:83–8.

    Article  CAS  PubMed  Google Scholar 

  • Kim YK, Yang EJ, Cho K, Lim JY, Paik N-J. Functional recovery after ischemic stroke is associated with reduced GABAergic inhibition in the cerebral cortex: a GABA PET study. Neurorehabil Neural Repair. 2014;28(6):576–83.

    Article  PubMed  Google Scholar 

  • Knake S, Hamer H, Schomburg U, Oertel W, Rosenow F. Tiagabine-induced absence status in idiopathic generalized epilepsy. Seizure. 1999;8:314–7.

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi T, Suemasa A, Igawa A, Ide S, Fukuda H, Abe H, et al. Conformationally restricted GABA with bicyclo[3.1.0]hexane backbone as the first highly selective BGT-1 inhibitor. ACS Med Chem Lett. 2014;5(8):889–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kong S, Cheng Z, Liu J, Wang Y. Downregulated GABA and BDNF-TrkB pathway in chronic cyclothiazide seizure model. Neural Plast. 2014;2014:9–11.

    Article  CAS  Google Scholar 

  • Kostandy BB. The role of glutamate in neuronal ischemic injury: the role of spark in fire. Neurol Sci. 2012;33(2):223–37.

    Article  PubMed  Google Scholar 

  • Kragholm B, Kvist T, Madsen KK, Jørgensen L, Vogensen SB, Schousboe A, et al. Discovery of a subtype selective inhibitor of the human betaine/GABA transporter 1 (BGT-1) with a non-competitive pharmacological profile. Biochem Pharmacol. 2013;86(4):521–8.

    Article  CAS  PubMed  Google Scholar 

  • Kristensen AS, Andersen J, Jørgensen TN, Sørensen L, Eriksen J, Loland CJ, et al. SLC6 neurotransmitter transporters: structure, function, and regulation. Pharmacol Rev. 2011;63(3):585–640.

    Article  CAS  PubMed  Google Scholar 

  • Kristensen BW, Noraberg J, Zimmer J. The GABAA receptor agonist THIP is neuroprotective in organotypic hippocampal slice cultures. Brain Res. 2003;973(2):303–6.

    Article  CAS  PubMed  Google Scholar 

  • Kälviäinen R. Long-term safety of tiagabine. Epilepsia. 2001;42(Suppl 1):46–9.

    Article  PubMed  Google Scholar 

  • Kälviäinen R. Tiagabine. Clinical efficacy and use in epilepsy. In: Antiepileptic drugs. 5th ed. New York: Raven Press; 2002. p. 698–704.

    Google Scholar 

  • Lake EMR, Chaudhuri J, Thomason L, Janik R, Ganguly M, Brown M, et al. The effects of delayed reduction of tonic inhibition on ischemic lesion and sensorimotor function. J Cereb Blood Flow Metab. 2015;35(10):1601–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lamar CD, Hurley RA, Rowland JA, Taber KH. Post-traumatic epilepsy: review of risks, pathophysiology, and potential biomarkers. J Neuropsychiatr Clin Neurosci. 2014;26(2):108–13.

    Article  Google Scholar 

  • Lazar RM, Fitzsimmons B-F, Marshall RS, Berman MF, Bustillo MA, Young WL, et al. Reemergence of stroke deficits with midazolam challenge. Stroke. 2002;33(1):283–5.

    Article  CAS  PubMed  Google Scholar 

  • Lee M, McGeer E, McGeer P. Mechanisms of GABA release from human astrocytes. Glia. 2011;59(11):1600–11.

    Article  PubMed  Google Scholar 

  • Lee TS, Bjørnsen LP, Paz C, Kim JH, Spencer SS, Spencer DD, et al. GAT1 and GAT3 expression are differently localized in the human epileptogenic hippocampus. Acta Neuropathol. 2006;111(4):351–63.

    Article  CAS  PubMed  Google Scholar 

  • Lee V, Maguire J. The impact of tonic GABAA receptor-mediated inhibition on neuronal excitability varies across brain region and cell type. Front Neural Circuits. 2014;8(3):1–27.

    Google Scholar 

  • Lehre AC, Rowley NM, Zhou Y, Holmseth S, Guo C, Holen T, et al. Deletion of the betaine-GABA transporter (BGT1; slc6a12) gene does not affect seizure thresholds of adult mice. Epilepsy Res. 2011;95(1–2):70–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lerma J, Herreras O, Herranz AS, Munoz D, del Rio RM. In vivo effects of nipecotic acid on levels of extracellular gaba and taurine, and hippocampal excitability. Neuropharmacology. 1984;23(5):595–8.

    Article  CAS  PubMed  Google Scholar 

  • Li C, Yan Z, Yang J, Chen H, Li H, Jiang Y, et al. Neuroprotective effects of resveratrol on ischemic injury mediated by modulating the release of neurotransmitter and neuromodulator in rats. Neurochem Int. 2010a;56(3):495–500.

    Article  CAS  PubMed  Google Scholar 

  • Li H, Li C, Yan Z-Y, Yang J, Chen H. Simultaneous monitoring multiple neurotransmitters and neuromodulators during cerebral ischemia/reperfusion in rats by microdialysis and capillary electrophoresis. J Neurosci Methods. 2010b;189(2):162–8.

    Article  CAS  PubMed  Google Scholar 

  • Li H, Zhang N, Lin HY, Yu Y, Cai QY, Ma L, et al. Histological, cellular and behavioral assessments of stroke outcomes after photothrombosis-induced ischemia in adult mice. BMC Neurosci. 2014;15(58):1–13.

    Google Scholar 

  • Lim DH, LeDue JM, Mohajerani MH, Murphy TH. Optogenetic mapping after stroke reveals network-wide scaling of functional connections and heterogeneous recovery of the peri-infarct. J Neurosci. 2014;34(49):16455–66.

    Article  CAS  PubMed  Google Scholar 

  • Liu S, Wang Y, Worley PF, Mattson MP, Gaiano N. The canonical Notch pathway effector RBP-J regulates neuronal plasticity and expression of GABA transporters in hippocampal networks. Hippocampus. 2015;25(5):670–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lo EH. A new penumbra: transitioning from injury into repair after stroke. Nat Med. 2008;14(5):497–500.

    Article  CAS  PubMed  Google Scholar 

  • Macdonald R, Barker JL. Benzodiazepines specifically modulate GABA-mediated postsynaptic inhibition in cultured mammalian neurones. Nature. 1978;271(5645):563–4.

    Article  CAS  PubMed  Google Scholar 

  • Madsen KK, Clausen RP, Larsson OM, Krogsgaard-Larsen P, Schousboe A, Steve WH. Synaptic and extrasynaptic GABA transporters as targets for anti-epileptic drugs. J Neurochem. 2009;109(Suppl. 1):139–44.

    Article  CAS  PubMed  Google Scholar 

  • Madsen KK, Ebert B, Clausen RP, Krogsgaard-Larsen P, Schousboe A, White HS. Selective GABA transporter inhibitors tiagabine and EF1502 exhibit mechanistic differences in their ability to modulate the ataxia and anticonvulsant action of the extrasynaptic GABAA receptor agonist gaboxadol. J Pharmacol Exp Ther. 2011;338(1):214–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Madsen KK, White HS, Schousboe A. Neuronal and non-neuronal GABA transporters as targets for antiepileptic drugs. Pharmacol Ther. 2010;125(3):394–401.

    Article  CAS  PubMed  Google Scholar 

  • Mao X, Guo F, Yu J, Min D, Wang Z, Xie N, et al. Up-regulation of GABA transporters and GABAA receptor α1 subunit in tremor rat hippocampus. Neurosci Lett. 2010;486(3):150–5.

    Article  CAS  PubMed  Google Scholar 

  • Mathern GW, Mendoza D, Lozada A, Pretorius JK, Dehnes Y, Danbolt NC, et al. Hippocampal GABA and glutamate transporter immunoreactivity in patients with temporal lobe epilepsy. Neurology. 1999;52(3):453–72.

    Article  CAS  PubMed  Google Scholar 

  • Medina-Ceja L, Sandoval-García F, Morales-Villagrán A, López-Pérez SJ. Rapid compensatory changes in the expression of EAAT-3 and GAT-1 transporters during seizures in cells of the CA1 and dentate gyrus. J Biomed Sci. 2012;19(78):1–11.

    Google Scholar 

  • Meldrum BS, Horton RW. Convulsive effects of 4-deoxypyridoxine and of bicuculline in photosensitive baboons (Papio papio) and in rhesus monkeys (Macaca mulatta). Brain Res. 1971;35(2):419–36.

    Article  CAS  PubMed  Google Scholar 

  • Melone M, Barbaresi P, Fattorini G, Conti F. Neuronal localization of the GABA transporter GAT-3 in human cerebral cortex: a procedural artifact? J Chem Neuroanat. 2005;30(1):45–54.

    Article  CAS  PubMed  Google Scholar 

  • Melone M, Cozzi A, Pellegrini-Giampietro DE, Conti F. Transient focal ischemia triggers neuronal expression of GAT-3 in the rat perilesional cortex. Neurobiol Dis. 2003;14(1):120–32.

    Article  CAS  PubMed  Google Scholar 

  • Murphy TH, Corbett D. Plasticity during stroke recovery: from synapse to behaviour. Nat Rev Neurosci. 2009;10(12):861–72.

    Article  CAS  PubMed  Google Scholar 

  • Nagatomo K, Ueda Y, Doi T, Takaki M, Tsuru N. Functional role of GABA transporters for kindling development in GLAST KO mice. Neurosci Res. 2007;57(2):319–21.

    Article  CAS  PubMed  Google Scholar 

  • Naquet R, Soulayrol R, Dolce G, Tassinari C, Broughton R, Loeb H. First attempt at treatment of experimental status epilepticus in animals and spontaneous status epilepticus in man with diazepam. Electroencephalogr Clin Neurophysiol. 1965;18:424–7.

    Article  Google Scholar 

  • Nelson RM, Green AR, Lambert DG, Hainsworth AH. On the regulation of ischaemia-induced glutamate efflux from rat cortex by GABA; in vitro studies with GABA, clomethiazole and pentobarbitone. Br J Pharmacol. 2000;130(5):1124–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nielsen EB, Suzdak PD, Andersen KE, Knutsen LJS, Sonnewald U, Braestrup C. Characterization of tiagabine (NO-328), a new potent and selective GABA uptake inhibitor. Eur J Pharmacol. 1991;196(3):257–66.

    Article  CAS  PubMed  Google Scholar 

  • O’Connell AW, Fox GB, Kjøller C, Gallagher HC, Murphy KJ, Kelly J, et al. Anti-ischemic and cognition-enhancing properties of NNC-711, γ-aminobutyric acid reuptake inhibitor. Eur J Pharmacol. 2001;424(1):37–44.

    Article  PubMed  Google Scholar 

  • Olsen M, Sarup A, Larsson OMOM, Schousboe A. Effect of hyperosmotic conditions on the expression of the betaine-GABA-transporter (BGT-1) in cultured mouse astrocytes. Neurochem Res. 2005;30(6–7):855–65.

    Article  CAS  PubMed  Google Scholar 

  • Olsen RW, Avoli M. GABA and epileptogenesis. Epilepsia. 1997;38(4):399–407.

    Article  CAS  PubMed  Google Scholar 

  • Orozco-Suarez S, Brunson KL, Feria-Velasco A, Ribak CE. Increased expression of γ-aminobutyric acid transporter-1 in the forebrain of infant rats with corticotropin-releasing hormone-induced seizures but not in those with hyperthermia-induced seizures. Epilepsy Res. 2000;42(2–3):141–57.

    Article  CAS  PubMed  Google Scholar 

  • Orser BA. Extrasynaptic GABAA receptors are critical targets for sedative-hypnotic drugs. J Clin Sleep Med. 2006;2(2):S12–8.

    PubMed  Google Scholar 

  • Ouyang C, Guo L, Lu Q, Xu X, Wang H. Enhanced activity of GABA receptors inhibits glutamate release induced by focal cerebral ischemia in rat striatum. Neurosci Lett. 2007;420(2):174–8.

    Article  CAS  PubMed  Google Scholar 

  • Pabel J, Faust M, Prehn C, Wörlein B, Allmendinger L, Höfner G, et al. Development of an (S)-1-{2-[tris(4-methoxyphenyl)methoxy]ethyl}piperidine-3-carboxylic acid [(S)-SNAP-5114] carba analogue inhibitor for murine γ-aminobutyric acid transporter type 4. ChemMedChem. 2012;7(7):1245–55.

    Article  CAS  PubMed  Google Scholar 

  • Patrylo PR, Spencer DD, Williamson A. GABA uptake and heterotransport are impaired in the dentate gyrus of epileptic rats and humans with temporal lobe sclerosis. J Neurophysiol. 2001;85(4):1533–42.

    CAS  PubMed  Google Scholar 

  • Pavlov I, Walker MC. Tonic GABAA receptor-mediated signalling in temporal lobe epilepsy. Neuropharmacology. 2013;69:55–61.

    Article  CAS  PubMed  Google Scholar 

  • Petersen JG, Sørensen T, Damgaard M, Nielsen B, Jensen AA, Balle T, et al. Synthesis and pharmacological evaluation of 6-aminonicotinic acid analogues as novel GABAA receptor agonists. Eur J Med Chem. 2014;84:404–16.

    Article  CAS  PubMed  Google Scholar 

  • Phillis JW. CI-966, a GABA uptake inhibitor, antagonizes ischemia-induced neuronal degeneration in the gerbil. Gen Pharmacol. 1995;26(5):1061–4.

    Article  CAS  PubMed  Google Scholar 

  • Pirttimaki T, Parri HR, Crunelli V. Astrocytic GABA transporter GAT-1 dysfunction in experimental absence seizures. J Physiol. 2013;591(4):823–33.

    Article  CAS  PubMed  Google Scholar 

  • Pitkänen A, Löscher W, Vezzani A, Becker AJ, Simonato M, Lukasiuk K, et al. Advances in the development of biomarkers for epilepsy. Lancet Neurol. 2016;15(8):843–56.

    Article  PubMed  CAS  Google Scholar 

  • Princivalle AP, Duncan JS, Thom M, Bowery NG. GABAB1a, GABAB1b and GABAB2 mRNA variants expression in hippocampus resected from patients with temporal lobe epilepsy. Neuroscience. 2003a;122(4):975–84.

    Article  CAS  PubMed  Google Scholar 

  • Princivalle AP, Richards DA, Duncan JS, Spreafico R, Bowery NG. Modification of GABAB1 and GABAB2 receptor subunits in the somatosensory cerebral cortex and thalamus of rats with absence seizures (GAERS). Epilepsy Res. 2003b;55(1–2):39–51.

    Article  CAS  PubMed  Google Scholar 

  • Rassner MP, Moser A, Follo M, Joseph K, van Velthoven-Wurster V, Feuerstein TJ. Neocortical GABA release at high intracellular sodium and low extracellular calcium: an anti-seizure mechanism. J Neurochem. 2016;137(2):177–89.

    Article  CAS  PubMed  Google Scholar 

  • Redecker C, Wang W, Fritschy J-M, Witte OW. Widespread and long-lasting alterations in GABAA-receptor subtypes after focal cortical infarcts in rats: mediation by NMDA-dependent processes. J Cereb Blood Flow Metab. 2002;22(12):1463–75.

    Article  CAS  PubMed  Google Scholar 

  • Richerson GB, Wu Y. Dynamic equilibrium of neurotransmitter transporters: not just for reuptake anymore. J Neurophysiol. 2003;90(3):1363–74.

    Article  CAS  PubMed  Google Scholar 

  • Rowley NM, Smith MD, Lamb JG, Schousboe A, White HS. Hippocampal betaine/GABA transporter mRNA expression is not regulated by inflammation or dehydration post-status epilepticus. J Neurochem. 2011;117(1):82–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Santhakumar V, Jones RT, Mody I. Developmental regulation and neuroprotective effects of striatal tonic GABAA currents. Neuroscience. 2010;167(3):644–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schallert T, Hernandez TD, Barth TM. Recovery of function after brain damage: severe and chronic disruption by diazepam. Brain Res. 1986;379(1):104–11.

    Article  CAS  PubMed  Google Scholar 

  • Schallert T, Jones T, Weaver M, Shapiro L, Crippens D, Fulton R. Pharmacologic and anatomic considerations in recovery of function. Phys Med Rehabil. 1992;6(3):375–89.

    Google Scholar 

  • Scharfman HE. The neurobiology of epilepsy. Curr Neuro Neurosci Rep. 2007;7(4):348–54.

    Article  CAS  Google Scholar 

  • Schijns O, Karaca Ü, Andrade P, de Nijs L, Küsters B, Peeters A, et al. Hippocampal GABA transporter distribution in patients with temporal lobe epilepsy and hippocampal sclerosis. J Chem Neuroanat. 2015;68:39–44.

    Article  CAS  PubMed  Google Scholar 

  • Schipper S, Aalbers MW, Rijkers K, Swijsen A, Rigo JM, Hoogland G, et al. Tonic GABAA receptors as potential target for the treatment of temporal lobe epilepsy. Mol Neurobiol. 2016;53(8):5252–65.

    Article  CAS  PubMed  Google Scholar 

  • Schousboe A. Role of astrocytes in the maintenance and modulation of glutamatergic and GABAergic neurotransmission. Neurochem Res. 2003;28(2):347–52.

    Article  CAS  PubMed  Google Scholar 

  • Schousboe A, Larsson OM, Wood JD, Krogsgaard-Larsen P. Transport and metabolism of γ-aminobutyric acid in neurons and glia: implications for epilepsy. Epilepsia. 1983;24(5):531–8.

    Article  CAS  PubMed  Google Scholar 

  • Schousboe A, Madsen KK, White HS. GABA transport inhibitors and seizure protection: the past and future. Future Med Chem. 2011;3(2):183–7.

    Article  CAS  PubMed  Google Scholar 

  • Schousboe A, Wellendorph P, Frølund B, Clausen RP, Krogsgaard-Larsen P. Astrocytic GABA-transporters: pharmacological properties and targets for antiepileptic drugs. In: Ortega A, Schousboe A, editors. Glial amino acid transporters. Cham: Springer; in press.

    Google Scholar 

  • Schwartz-Bloom RD, Sah R. γ-Aminobutyric acidA neurotransmission and cerebral ischemia. J Neurochem. 2001;77(2):353–71.

    Article  CAS  PubMed  Google Scholar 

  • Shaju M, Abraham S. Innovations in epilepsy management - an overview. J Pharm Pharm Sci. 2013;16(4):564–76.

    Article  PubMed  Google Scholar 

  • Smith MD, Saunders GW, Clausen RP, Frølund B, Krogsgaard-Larsen P, Larsson OM, et al. Inhibition of the betaine-GABA transporter (mGAT2/BGT-1) modulates spontaneous electrographic bursting in the medial entorhinal cortex (mEC). Epilepsy Res. 2008;79(1):6–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sofroniew MV. Astrocyte barriers to neurotoxic inflammation. Nat Rev Neurosci. 2015;16(5):249–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol. 2010;119(1):7–35.

    Article  PubMed  Google Scholar 

  • Song I, Volynski K, Brenner T, Ushkaryov Y, Walker M, Semyanov A. Different transporter systems regulate extracellular GABA from vesicular and non-vesicular sources. Front Cell Neurosci. 2013;7(23):1–7.

    Google Scholar 

  • Southan C, Sharman JL, Benson HE, Faccenda E, Pawson AJ, Alexander SPH, et al. The IUPHAR/BPS Guide to Pharmacology in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. Nucleic Acids Res. 2016;44(D1):D1054–68.

    Article  CAS  PubMed  Google Scholar 

  • Sperk G, Schwarzer C, Heilman J, Furtinger S, Reimer RJ, Edwards RH, et al. Expression of plasma membrane GABA transporters but not of the vesicular GABA transporter in dentate granule cells after kainic acid seizures. Hippocampus. 2003;13(7):806–15.

    Article  CAS  PubMed  Google Scholar 

  • Spreafico R, Tassi L, Colombo N, Bramerio M, Galli C, Garbelli R, et al. Inhibitory circuits in human dysplastic tissue. Epilepsia. 2000;41(Suppl. 6):S168–73.

    Article  PubMed  Google Scholar 

  • Staley K. Molecular mechanisms of epilepsy. Nat Neurosci. 2015;18(3):367–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Su J, Yin J, Qin W, Sha S, Xu J, Jiang C. Role for pro-inflammatory cytokines in regulating expression of GABA transporter type 1 and 3 in specific brain regions of kainic acid-induced status epilepticus. Neurochem Res. 2015;40(3):621–7.

    Article  CAS  PubMed  Google Scholar 

  • Sutch RJ, Davies CC, Bowery NG. GABA release and uptake measured in crude synaptosomes from Genetic Absence Epilepsy Rats from Strasbourg (GAERS). Neurochem Int. 1999;34(5):415–25.

    Article  CAS  PubMed  Google Scholar 

  • Thomsen C, Sørensen PO, Egebjerg J. 1-(3-(9H-carbazol-9-yl)-1-propyl)-4-(2-methoxyphenyl)-4-piperidinol, a novel subtype selective inhibitor of the mouse type II GABA-transporter. Br J Pharmacol. 1997;120(6):983–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Treiman DM. GABAergic mechanisms in epilepsy. Epilepsia. 2001;42(Suppl. 3):8–12.

    Article  PubMed  Google Scholar 

  • Trojnar MK, Małek R, Chrościńska M, Nowak S, Błaszczyk B, Czuczwar SJ. Neuroprotective effects of antiepileptic drugs. Pol J Pharmacol. 2002;54(6):557–66.

    CAS  PubMed  Google Scholar 

  • Ueda Y, Willmore LJ. Hippocampal γ-aminobutyric acid transporter alterations following focal epileptogenesis induced in rat amygdala. Brain Res Bull. 2000;52(5):357–61.

    Article  CAS  PubMed  Google Scholar 

  • Usunoff G, Atsev E, Tchavdarov D. On the mechanisms of picrotoxin epileptic seizure (macro- and micro-electrode investigations). Electroencephalogr Clin Neurophysiol. 1969;27(4):444.

    Article  CAS  PubMed  Google Scholar 

  • Vinton A, Kornberg A, Cowley M, Matkovic Z, Kilpatrick C, O’Brien T. Tiagabine-induced generalised non convulsive status epilepticus in patients with lesional focal epilepsy. J Clin Neurosci. 2005;12(2):128–33.

    Article  CAS  PubMed  Google Scholar 

  • Vogensen SB, Jørgensen L, Madsen KK, Borkar N, Wellendorph P, Skovgaard-Petersen J, et al. Selective mGAT2 (BGT-1) GABA uptake inhibitors: design, synthesis, and pharmacological characterization. J Med Chem. 2013;56(5):2160–4.

    Article  CAS  PubMed  Google Scholar 

  • Wang J-G, Cai Q, Zheng J, Dong Y-S, Li J-J, Li J-C, et al. Epigenetic suppression of GADs expression is involved in temporal lobe epilepsy and pilocarpine-induced mice epilepsy. Neurochem Res. 2016;41(7):1751–60.

    Article  CAS  PubMed  Google Scholar 

  • Wellendorph P, Jacobsen J, Skovgaard-Petersen J, Jurik A, Vogensen SB, Ecker G, Schousboe A, Krogsgaard-Larsen P, Clausen RP. γ-Aminobutyric acid and glycine neurotransmitter transporters. In: Sitte HH, Ecker GF, Folkers G, Mannhold R, Buschmann H, Clausen RP, editors. Transporters as drug targets. Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA; 2017. doi:10.1002/9783527679430.ch4.

    Google Scholar 

  • White HS, Hunt J, Wolf HH, Swinyard EA, Falch E, Krogsgaard-Larsen P, et al. Anticonvulsant activity of the γ-aminobutyric acid uptake inhibitor N-4,4-diphenyl-3-butenyl-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol. Eur J Pharmacol. 1993;236(1):147–9.

    Article  CAS  PubMed  Google Scholar 

  • White HS, Sarup A, Bolvig T, Kristensen AS, Petersen G, Nelson N, et al. Correlation between anticonvulsant activity and inhibitory action on glial γ-aminobutyric acid uptake of the highly selective mouse γ-aminobutyric acid transporter 1 inhibitor 3-hydroxy-4-amino-4,5,6,7-tetrahydro-1,2-benzisoxazole and its N-alkylated anal. J Pharmacol Exp Ther. 2002;302(2):636–44.

    Article  CAS  PubMed  Google Scholar 

  • White HS, Watson WP, Hansen SL, Slough S, Perregaard J, Sarup A, et al. First demonstration of a functional role for central nervous system betaine/γ-aminobutyric acid transporter (mGAT2) based on synergistic anticonvulsant action among inhibitors of mGAT1 and mGAT2. J Pharmacol Exp Ther. 2005;312(2):866–74.

    Article  CAS  PubMed  Google Scholar 

  • World Health Federation. Stroke [Internet]. 2016 [cited 2016 Sept 1]. Available from: www.world-heart-federation.org/cardiovascular-health/stroke/

  • WHO. Epilepsy Fact Sheet [Internet]. 2016a [cited 2016 Jun 30]. Available from: www.who.int/mediacentre/factsheets/fs999/en/

  • WHO. The top 10 causes of death Fact Sheet [Internet]. 2016b [cited 2016 Jun 30]. Available from: www.who.int/mediacentre/factsheets/fs310/en/

  • Wood JD, Johnson DD, Krogsgaard-Larsen P, Schousboe A. Anticonvulsant activity of the glial-selective GABA uptake inhibitor, THPO. Neuropharmacology. 1983;22(1):139–42.

    Article  CAS  PubMed  Google Scholar 

  • Wu Z, Guo Z, Gearing M, Chen G. Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzhiemer’s disease model. Nat Commun. 2014;5(4159):1–13.

    Google Scholar 

  • Yang Y, Li Q, Wang CX, Jeerakathil T, Shuaib A. Dose-dependent neuroprotection with tiagabine in a focal cerebral ischemia model in rat. Neuroreport. 2000;11(10):2307–11.

    Article  CAS  PubMed  Google Scholar 

  • Yasiry Z, Shorvon SD. How phenobarbital revolutionized epilepsy therapy: the story of phenobarbital therapy in epilepsy in the last 100 years. Epilepsia. 2012;53(Suppl 8):26–39.

    Article  CAS  PubMed  Google Scholar 

  • Yunger LM, Fowler PJ, Zarevics P, Setler PE. Novel inhibitors of γ-aminobutyric acid (GABA) uptake: anticonvulsant actions in rats and mice. J Pharmacol Exp Ther. 1984;228(1):109–15.

    CAS  PubMed  Google Scholar 

  • Zhou Y, Holmseth S, Hua R, Lehre AC, Olofsson AM, Poblete-Naredo I, et al. The betaine-GABA transporter (BGT1, slc6a12) is predominantly expressed in the liver and at lower levels in the kidneys and at the brain surface. AJP Ren Physiol. 2012;302(3):316–28.

    Article  CAS  Google Scholar 

  • Zhu XM, Ong WY. Changes in GABA transporters in the rat hippocampus after kainate-induced neuronal injury: decrease in GAT-1 and GAT-3 but upregulation of betaine/GABA transporter BGT-1. J Neurosci Res. 2004a;77(3):402–9.

    Article  CAS  PubMed  Google Scholar 

  • Zhu XM, Ong WY. A light and electron microscopic study of betaine/GABA transporter distribution in the monkey cerebral neocortex and hippocampus. J Neurocytol. 2004b;33(2):233–40.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Maria E.K. Lie and Anas Al-Khawaja contributed equally to this work.

Authors and Affiliations

  1. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark

    Maria E. K. Lie, Anas Al-Khawaja, Maria Damgaard, Anne S. Haugaard, Arne Schousboe & Petrine Wellendorph

  2. Department of Anatomy, Brain Health Research Centre and Brain Research New Zealand, University of Otago, 9054, Dunedin, New Zealand

    Andrew N. Clarkson

  3. Faculty of Pharmacy, The University of Sydney, Sydney, NSW, 2006, Australia

    Andrew N. Clarkson

Authors
  1. Maria E. K. Lie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anas Al-Khawaja
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria Damgaard
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anne S. Haugaard
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Arne Schousboe
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andrew N. Clarkson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Petrine Wellendorph
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Petrine Wellendorph .

Editor information

Editors and Affiliations

  1. Department of Toxicology, Cinvestav-IPN México City, México, Mexico

    Arturo Ortega

  2. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Arne Schousboe

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Lie, M.E.K. et al. (2017). Glial GABA Transporters as Modulators of Inhibitory Signalling in Epilepsy and Stroke. In: Ortega, A., Schousboe, A. (eds) Glial Amino Acid Transporters. Advances in Neurobiology, vol 16. Springer, Cham. https://doi.org/10.1007/978-3-319-55769-4_7

Download citation

Publish with us

Policies and ethics

Search

Navigation