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GABAergic Neurotransmission Abnormalities in Pharmacoresistant Epilepsy: Experimental and Human Studies

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Pharmacoresistance in Epilepsy

Abstract

Despite the fact that there are several drugs available for the treatment of epilepsy, pharmacoresistance remains a major challenge in seizure control. Therefore, a significant part of epilepsy research has focused on revealing the mechanisms underlying drug resistance in order to develop new rationally designed pharmaceutical therapies for refractory epilepsies. Based on experimental and clinical studies, epilepsy-induced structural and functional alterations in brain targets have been postulated to lead to decreased sensitivity to antiepileptic drugs, more recently antiseizure medications (ASM). Also, evidence shows that GABA neurotransmission system plays a leading role in the pathophysiology of epilepsy. Canonically, GABA (gamma-aminobutyric acid) is considered the main inhibitory neurotransmitter in the central nervous system, but due to the variability in the location and composition of its receptors by different types of subunits, as well as neural physiological immaturity, GABA may have excitatory effects. Abnormalities in the GABAergic system identified in animal models of epilepsy and in samples of brain tissue samples resected surgically from patients with drug-resistant epilepsy, mainly at level of GABAA receptors (GABAARs), whose changes lead to an altered response to some ASMs, among other neuroleptic drugs.

Here we review the current evidence on changes in the GABAergic system related to seizure generation, epilepsy, and pharmacoresistance, with particular emphasis on GABAARs and genetic polymorphisms of its subunits associated with refractory human epilepsy.

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References

  • Alfano V, Romagnolo A, Mills JD, Cifelli P, Gaeta A, Morano A, Mühlebner A, Aronica E, Palma E, Ruffolo G. Unexpected effect of IL-1β on the function of GABAA receptors in pediatric focal cortical dysplasia. Brain Sci. 2022;12(6):807. https://doi.org/10.3390/brainsci12060807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Almeida AC, Scorza FA, Rodríguez AM, Arida RM, Carlesso FN, Batista AG, et al. Combined effect of bumetanide, bromide, and GABAergic agonists: an alternative treatment for intractable seizures. Epilepsy Behav. 2011;20:147–9.

    Article  PubMed  Google Scholar 

  • Antrobus SP, Lytle C, Payne JA. K+-Cl- cotransporter-2 KCC2 in chicken cardiomyocytes. Am J Physiol Cell Physiol. 2012;303(11):C1180–91. https://doi.org/10.1152/ajpcell.00274.2012.

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

    Article  CAS  PubMed  Google Scholar 

  • Audenaert D, Schwartz E, Claeys KG, Claes L, Deprez L, Suls A, et al. Combined effect of bumetanide, bromide, and GABAergic agonists: an alternative treatment for intractable seizures. Epilepsy Behav. 2011;20:147–9.

    Google Scholar 

  • Avoli M, Lévesque M. GABAB receptors: are they missing in action in focal epilepsy research? Curr Neuropharmacol. 2022;20(9):1704–16. https://doi.org/10.2174/1570159X19666210823102332. PMID: 34429053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bakas T, van Nieuwenhuijzen PS, Devenish SO, McGregor IS, Arnold JC, Chebib M. The direct actions of cannabidiol and 2-arachidonoyl glycerol at GABAA receptors. Pharmacol Res. 2017;119:358–70. https://doi.org/10.1016/j.phrs.2017.02.022.

    Article  CAS  PubMed  Google Scholar 

  • Barker JS, Hines RM. Regulation of GABAA receptor subunit expression in substance use disorders. Int J Mol Sci. 2020;21(12):4445. https://doi.org/10.3390/ijms21124445.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barnard EA, Skolnick P, Olsen RW, Mδhler H, Sieghart W, Biggio G, et al. International Union of Pharmacology. XV. Subtypes of GABA receptors: classification on the basis of subunit structure and receptor function. Pharmacol Rev. 1998;50:291–313.

    CAS  PubMed  Google Scholar 

  • Bazhanova ED, Kozlov AA, Litovchenko AV. Mechanisms of drug resistance in the pathogenesis of epilepsy: role of neuroinflammation. A literature review. Brain Sci. 2021;11(5):663. https://doi.org/10.3390/brainsci11050663.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Belhage B, Hansen GH, Schousboe A. Depolarization by K+ and glutamate activates different neurotransmitter release mechanisms in GABAergic neurons: vesicular versus non-vesicular release of GABA. Neuroscience. 1993;54:1019–34.

    Article  CAS  PubMed  Google Scholar 

  • Ben-Ari Y. Blocking seizures with the diuretic bumetanide: promises and pitfalls. Epilepsia. 2012;53(2):394–6.

    Article  PubMed  Google Scholar 

  • Ben-Ari Y, Giarsa JL, Tyzio R, Khazipov R. GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations. Physiol Rev. 2007;87:1215–84.

    Article  CAS  PubMed  Google Scholar 

  • Ben-Ari Y, Khalilov I, Kahle KT, Cherubini E. The GABA excitatory/inhibitory shift in brain maturation and neurological disorders. Neuroscientist. 2012;18(5):467–86.

    Article  PubMed  Google Scholar 

  • Ben-Ari Y, Damier P, Lemonnier E. Failure of the nemo trial: bumetanide is a promising agent to treat many brain disorders but not newborn seizures. Front Cell Neurosci. 2016;10:90. https://doi.org/10.3389/fncel.2016.00090.

    Article  PubMed  PubMed Central  Google Scholar 

  • Benarroch E. GABAB receptors structure, functions, and clinical implications. Neurology. 2012;78:578–82.

    Article  CAS  PubMed  Google Scholar 

  • Blaesse P, Airaksinen MS, Rivera C, Kaila K. Cation-chloride cotransporters and neuronal function. Neuron. 2009;61:820–38.

    Article  CAS  PubMed  Google Scholar 

  • Blauwblomme T, Dossi E, Pellegrino C, Goubert E, Iglesias BG, Sainte-Rose C, Rouach N, Nabbout R, Huberfeld G. Gamma-aminobutyric acidergic transmission underlies interictal epileptogenicity in pediatric focal cortical dysplasia. Ann Neurol. 2019;85:204–17.

    Article  CAS  PubMed  Google Scholar 

  • Blumcke I, Spreafico R, Haaker G, Coras R, Kobow K, Bien CG, Pfäfflin M, Elger C, Widman G, Schramm J, et al. Histopathological findings in brain tissue obtained during epilepsy surgery. N Engl J Med. 2017;377:1648–56.

    Article  PubMed  Google Scholar 

  • Bormann J. Electrophysiology of GABAA and GABAB receptor subtypes. Trends Neurosci. 1988;11:112–6.

    Article  CAS  PubMed  Google Scholar 

  • Bormann J, Feigenspan A. GABAC receptors. Trends Neurosci. 1995;18:515–9.

    Article  CAS  PubMed  Google Scholar 

  • Bowery NG. GABAB receptors and their significance in mammalian pharmacology. Trends Pharmacol Sci. 1989;10:401–7.

    Article  CAS  PubMed  Google Scholar 

  • Bragin DE, Sanderson JL, Peterson S, Connor JA, Müller WS. Development of epileptiform excitability in the deep entorhinal cortex after status epilepticus. Eur J Neurosci. 2009;30:611–24.

    Article  PubMed  PubMed Central  Google Scholar 

  • Briggs SW, Galanopoulou AS. Altered GABA signaling in early life epilepsies. Neural Plast. 2011;2011:527605.

    Article  PubMed  PubMed Central  Google Scholar 

  • Brodie MJ, Ben-Menachem E. Cannabinoids for epilepsy: what do we know and where do we go? Epilepsia. 2018;59:291–6.

    Article  PubMed  Google Scholar 

  • Brooks-Kayal AR, Shumate MD, Jin H, Rikhter TY, Coulter DA. Selective changes in single cell GABA(A) receptor subunit expression and function in temporal lobe epilepsy. Nat Med. 1998;4:1166–72.

    Article  CAS  PubMed  Google Scholar 

  • Buró D, Kamatchi G. GABAA receptor subtypes: from pharmacology to molecular biology. FASEB J. 1991;5:2916–23.

    Article  Google Scholar 

  • Butler KM, Moody OA, Schuler E, Coryell J, Alexander JJ, et al. De novo variants in GABRA2 and GABRA5 alter receptor function and contribute to early-onset epilepsy. Brain. 2018;141:2392–405.

    Article  PubMed  PubMed Central  Google Scholar 

  • Cancedda L, Fiumelli H, Chen K, Poo MM. Excitatory GABA action is essential for morphological maturation of cortical neurons in vivo. J Neurosci. 2007;27:5224–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carver CM, Reddy DS. Neurosteroid interactions with synaptic and extrasynaptic GABA-A receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability. Psychopharmacology (Berl). 2013;230(2):151–88.

    Article  CAS  PubMed  Google Scholar 

  • Carvill GL, Weckhuysen S, McMahon JM, Hartmann C, Møller RS, et al. GABRA1 and STXBP1: novel genetic causes of Dravet syndrome. Neurology. 2014;82:1245–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carvill GL, McMahon JM, Schneider A, Zemel M, Myers CT, et al. Mutations in the GABA transporter SLC6A1 cause epilepsy with myoclonic-atonic seizures. Am J Hum Genet. 2015;96:808–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Castro-Torres RD, Ureña-Guerrero ME, Morales-Chacón LM, Lorigados-Pedre L, Estupiñan-Díaz B, Rocha L, Orozco-Suárez S, Rivera-Cervantes MC, Alonso-Vanegas M, Beas-Zárate C. New aspects of VEGF, GABA, and glutamate signaling in the neocortex of human temporal lobe pharmacoresistant epilepsy revealed by RT-qPCR arrays. J Mol Neurosci. 2020 Jun;70(6):916–29. https://doi.org/10.1007/s12031-020-01519-6.

    Article  CAS  PubMed  Google Scholar 

  • Cepeda C, André VM, Levine MS, Salamon N, Miyata H, Vinters HV, Mathern GW. Epileptogenesis in pediatric cortical dysplasia: the dysmature cerebral developmental hypothesis. Epilepsy Behav. 2006;9:219–35.

    Article  PubMed  Google Scholar 

  • Cepeda C, Chen JY, Wu JY, Fisher RS, Vinters HV, Mathern GW, Levine MS. Pacemaker GABA synaptic activity may contribute to network synchronization in pediatric cortical dysplasia. Neurobiol Dis. 2014;62:208–17.

    Article  CAS  PubMed  Google Scholar 

  • Chen L, Wan L, Wu Z, Ren W, Huang Y, Qian B, Wang, Y. KCC2 downregulation facilitates epileptic seizures. Sci Rep. 2017;7(1):156. https://doi.org/10.1038/s41598-017-00196-7.

  • Cherubini E, Ben-Ari Y. The immature brain needs GABA to be excited and hyper-excited. J Physiol. 2011;589(Pt 10):2655–6. https://doi.org/10.1113/jphysiol.2011.208884.

  • Cifelli P, Ruffolo G, De Felice E, Alfano V, van Vliet EA, Aronica E, Palma E. Phytocannabinoids in neurological diseases: could they restore a physiological GABAergic transmission? Int J Mol Sci. 2020;21(3):723. https://doi.org/10.3390/ijms21030723.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cohen I, Navarro V, Clemenceau S, Baulac M, Miles R. On the origin of interictal activity in human temporal lobe epilepsy in vitro. Science. 2002;298:1418–21.

    Article  CAS  PubMed  Google Scholar 

  • Cossett P, Liu L, Brisebois K, Dong H, Lortie A, Vannase M, et al. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet. 2002;31:184–9.

    Article  Google Scholar 

  • Crino PB, Duhaime AC, Baltuch G, White R. Differential expression of glutamate and GABA-A receptor subunit mRNA in cortical dysplasia. Neurology. 2001;56:906–13.

    Article  CAS  PubMed  Google Scholar 

  • Devinsky O, Nabbout R, Miller I, Laux L, Zolnowska M, Wright S, Roberts C. Long-term cannabidiol treatment in patients with Dravet syndrome: an open-label extension trial. Epilepsia. 2019;60(2):294–302. https://doi.org/10.1111/epi.14628.

    Article  CAS  PubMed  Google Scholar 

  • Dibbens LM, Feng HJ, Richards MC, Harkin LA, Hudqson BL, Scott D, et al. GABRD encoding a protein for extra- or peri-synaptic GABA-A receptors is a susceptibility locus for generalized epilepsies. Hum Mol Genet. 2004;13:1315–9.

    Article  CAS  PubMed  Google Scholar 

  • Ding L, Feng HJ, Macdonald RL, Botzolakis EJ, Hu N, Gallagher MJ. GABA(A) receptor alpha−1 subunit mutation A322D associated with autosomal dominant juvenile myoclonic epilepsy reduces the expression and alters the composition of wild type GABA(A) receptors. J Biol Chem. 2010;285:26390–405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dzhala VI, Talos DM, Sdrulla DA, Brumback AC, Mathews GC, Benke TA, et al. NKCC1 transporter facilitates seizures in the developing brain. Nat Med. 2005;11:1205–13.

    Article  CAS  PubMed  Google Scholar 

  • Eftekhari S, Mehvari Habibabadi J, Najafi Ziarani M, Hashemi Fesharaki SS, Gharakhani M, Mostafavi H, et al. Bumetanide reduces seizure frequency in patients with temporal lobe epilepsy. Epilepsia. 2013;54:e9–12. https://doi.org/10.1111/j.1528-1167.2012.03654.x.

    Article  CAS  PubMed  Google Scholar 

  • Enz R, Cutting GR. Molecular composition of GABAC receptors. Vis Res. 1998;38:1431–41.

    Article  CAS  PubMed  Google Scholar 

  • Enz R, Cutting GR. GABAC receptor r subunits are heterogeneously expressed in the human CNS and form homo- and heterooligomers with distinct properties. Eur J Neurosci. 1999;11:41–50.

    Article  CAS  PubMed  Google Scholar 

  • Erker T, Brandt C, Töllner K, et al. The bumetanide prodrug BUM5, but not bumetanide, potentiates the antiseizure effect of phenobarbital in adult epileptic mice. Epilepsia. 2016;57(5):698–705.

    Article  CAS  PubMed  Google Scholar 

  • Erlander MG, Tillakaratne NJ, Feldblum S, Patel N, Tobin AJ. Two genes encode distinct glutamate decarboxylases. Neuron. 1991;7:91–100.

    Article  CAS  PubMed  Google Scholar 

  • EuroEPINOMICS-RES Consortium; Epilepsy Phenome/Genome Project; Epi4K Consortium. De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am J Hum Genet. 2014;95:360–70.

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Feigenspan A, Bormann J. GABA-gated Cl2 channels in the rat retina. Prog Retin Eye Res. 1998;17:99–126.

    Article  CAS  PubMed  Google Scholar 

  • French J, Thiele E, Mazurkiewicz-Beldzinska M, et al. Cannabidiol (CBD) significantly reduces drop seizure frequency in Lennox- Gastaut syndrome (LGS): results of a multi-center, randomized, double-blind, placebo controlled trial (GWPCARE4)(S21. 001). Neurology. 2017;88(16 Supplement):S21–S001.

    Google Scholar 

  • Fritschy JM, Kiener T, Bouilleret V, Loup F. GABAergic neurons and GABAA-receptors in temporal lobe epilepsy. Neurochem Int. 1999;34:435–45.

    Article  CAS  PubMed  Google Scholar 

  • Gerelsaikhan T, Turner RJ. Transmembrane topology of the secretory Na + -K + -2Cl – cotransporter NKCC1 studied by in vitro translation. J Biol Chem. 2000;275:40471–7.

    Article  CAS  PubMed  Google Scholar 

  • Gharaylou Z, Tafakhori A, Agah E, Aghamollaii V, Kebriaeezadeh A, Hadjighassem M. A preliminary study evaluating the safety and efficacy of bumetanide, an NKCC1 inhibitor, in patients with drug-resistant epilepsy. CNS Drugs. 2019;33(3):283–91. https://doi.org/10.1007/s40263-019-00607-5. Erratum in: CNS Drugs. 2019 Jul 23

    Article  CAS  PubMed  Google Scholar 

  • Gibbs JW III, Shumate M, Coulter D. Differential epilepsy-associated alterations in postsynaptic GABAA receptor function in dentate granule and CA1 neurons. J Neurophysiol. 1997;77:1924–38.

    Article  CAS  PubMed  Google Scholar 

  • Glykys J, Mody I. Hippocampal network hyperactivity after selective reduction of tonic inhibition in GABA A receptor alpha5 subunit-defi cient mice. J Neurophysiol. 2006;95:2796–807.

    Article  CAS  PubMed  Google Scholar 

  • Glykys J, Dzhala VI, Kuchibhotla KV, Feng G, Kuner T, Augustine G, et al. Differences in cortical versus subcortical GABAergic signaling a candidate mechanism of electroclinical uncoupling of neonatal seizures. Neuron. 2009;63:657–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Golub V, Ramakrishnan S, Reddy DS. Isobolographic analysis of adjunct antiseizure activity of the FDA-approved cannabidiol with neurosteroids and benzodiazepines in adult refractory focal onset epilepsy. Exp Neurol. 2023;360:114294. https://doi.org/10.1016/j.expneurol.2022.114294.

    Article  CAS  PubMed  Google Scholar 

  • Gulyas AI, Sik A, Payne JA, Kaila K, Freund TF. The KCI cotransporter, KCC2, is highly expressed in the vicinity of excitatory synapses in the rat hippocampus. Eur J Neurosci. 2001;13:2205–17.

    Article  CAS  PubMed  Google Scholar 

  • Hadingham KL, Wingrove P, Le Bourdelles B, Palmer KJ, Ragan CI, et al. Cloning of cDNA sequences encoding human alpha 2 and alpha 3 gamma-aminobutyric acid A receptor subunits and characterization of the benzodiazepine pharmacology of recombinant alpha 1-, alpha 2-, alpha 3-, and alpha 5-containing human gamma-aminobutyric acid A receptors. Mol Pharmacol. 1993;43:970–5.

    CAS  PubMed  Google Scholar 

  • Hamdan FF, Myers CT, Cossette P, Lemay P, Spiegelman D, et al. High rate of recurrent de novo mutations in developmental and epileptic encephalopathies. Am J Hum Genet. 2017;101:664–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harkin LA, Bowser DN, Dibbens LM, Singh R, Phillips F, Wallace RH, et al. Truncation of the GABA-A-receptor gamma-2 subunit in a family with generalized epilepsy with febrile seizures plus. Am J Hum Genet. 2002;70:530–6.

    Article  CAS  PubMed  Google Scholar 

  • Hernandez CC, XiangWei W, Hu N, Shen D, Shen W, Lagrange AH, et al. Altered inhibitory synapses in de novo GABRA5 and GABRA1 mutations associated with early onset epileptic encephalopathies. Brain. 2019;142:1938–54.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hertz L, Schousboe A. Primary cultures of GABAergic and glutamatergic neurons as model systems to study neurotransmitter functions. Differentiated cells. In: Vernadakis A, Privat A, Lauder JM, Timiras PS, Giacobini E, editors. Model systems of development and aging of the nervous system. Boston: Martinus Nijhoff Publishing; 1987.

    Google Scholar 

  • Hill DR, Bowery NG. 3H-baclofen and 3H-GABA bind to bicuculline-insensitive GABAB sites in rat brain. Nature. 1981;290:149–52.

    Article  CAS  PubMed  Google Scholar 

  • Hilton GD, Ndubuizu A, Nunez JL, McCarthy MM. Simultaneous glutamate and GABA(A) receptor agonist administration increases calbindin levels and prevents hippocampal damage induced by either agent alone in a model of perinatal brain injury. Brain Res Dev Brain Res. 2005;159:99–111.

    Article  CAS  PubMed  Google Scholar 

  • Houser CR, Esclapez M. Downregulation of the α5 subunit of the GABA a receptor in the pilocarpine model of temporal lobe epilepsy. Hippocampus. 2003;13:633–45. http://investor.sagerx.com/news-releases/news-release-details/sage-therapeutics-reports-top-line-results-phase-3-status-trial

    Article  CAS  PubMed  Google Scholar 

  • Iori V, Frigerio F, Vezzani A. Modulation of neuronal excitability by immune mediators in epilepsy. Curr Opin Pharmacol. 2016;26:118–23.

    Article  CAS  PubMed  Google Scholar 

  • Ishii A, Kang JQ, Schornak CC, Hernandez CC, Shen W, et al. A de novo missense mutation of GABRB2 causes early myoclonic encephalopathy. J Med Genet. 2017;54:202–11.

    Article  CAS  PubMed  Google Scholar 

  • Iversen LL, Kelly JS. Uptake and metabolism of gamma-aminobutyric acid by neurones and glial cells. Biochem Pharmacol. 1975;24:933–8.

    Article  CAS  PubMed  Google Scholar 

  • Jacob TC, Moss SJ, Jurd R. GABA(A) receptor trafficking and its role in the dynamic modulation of neuronal inhibition. Nat Rev Neurosci. 2008;9:331–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Janve VS, Hernandez CC, Verdier KM, Hu N, Macdonald RL. Epileptic encephalopathy de novo GABRB mutations impair γ-aminobutyric acid type A receptor function. Ann Neurol. 2016;79(5):806–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jensen FE. Neonatal seizures: an update on mechanisms and management. Clin Perinatol. 2009;36:881–900.

    Article  PubMed  PubMed Central  Google Scholar 

  • Johnston GA. GABAC receptors: relatively simple transmitter gated ion channels? Trends Pharmacol Sci. 1996;17:319–23.

    Article  CAS  PubMed  Google Scholar 

  • Josiah SS, Meor Azlan NF, Zhang J. Targeting the WNK-SPAK/OSR1 pathway and cation-chloride cotransporters for the therapy of stroke. Int J Mol Sci. 2021;22(3):1232. https://doi.org/10.3390/ijms22031232.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jullien V, Pressler RM, Boylan G, et al. Pilot evaluation of the population pharmacokinetics of bumetanide in term newborn infants with seizures. J Clin Pharmacol. 2016;56(3):284–90.

    Article  CAS  PubMed  Google Scholar 

  • Kaila K, Price TJ, Payne JA, Puskarjov M, Voipio J. Cation-chloride cotransporters in neuronal development, plasticity and disease. Nat Rev Neurosci. 2014;15(10):637–54. https://doi.org/10.1038/nrn3819.

  • Kahle KT, Staley KJ. Cation-chloride cotransporters as pharmacological targets in the treatment of epilepsy. In: Alvarez-Leefmans F, Delpire E, editors. Physiology and pathology of chloride transporters and channels in the nervous system. New York: Academic; 2009.

    Google Scholar 

  • Kahle KT, Barnett SM, Sassower KC, Staley KJ. Decreased seizure activity in a human neonate treated with bumetanide, an inhibitor of the Na(+)- K(+)-2Cl(−) cotransporter NKCC1. J Child Neurol. 2009;24:572–6. https://doi.org/10.1177/0883073809333526.

    Article  PubMed  Google Scholar 

  • Kahle KT, Deeb TZ, Puskarjov M, Silayeva L, Liang B, Kaila K, Moss SJ. Modulation of neuronal activity by phosphorylation of the K-Cl cotransporter KCC2. Trends Neurosci. 2013 Dec;36(12):726–737. https://doi.org/10.1016/j.tins.2013.08.006.

  • Kaminski RM, Livingood MR, Rogawski MA. Allopregnanolone analogs that positively modulate GABAA receptors protect against partial seizures induced by 6-Hz electrical stimulation in mice. Epilepsia. 2004;45(7):864–7.

    Article  CAS  PubMed  Google Scholar 

  • Kananura C, Haug K, Sander T, Runge U, Gu W, Hallmann K, et al. A splice-site mutation in GABRG2 associated with childhood absence epilepsy and febrile convulsions. Arch Neurol. 2002;59:1137–41.

    Article  PubMed  Google Scholar 

  • Kanes S, Rosenthal E, Vaitkevicius H, et al. 547-SSE-201 for superrefractory status epilepticus: response and relationship to underlying patient characteristics (S14. 003). Neurology. 2016;86(16 Suppl):S14–003.

    Google Scholar 

  • Kang I, Lindquist DG, Kinane TB, Ercolani L, Pritchard GA, et al. Isolation and characterization of the promoter of the human GABAA receptor alpha 1 subunit gene. J Neurochem. 1994;62:1643–6.

    Article  CAS  PubMed  Google Scholar 

  • Kang JQ, Shen W, Macdonald RL. Why does fever trigger febrile seizures? GABAA receptor gamma2 subunit mutations associated with idiopathic generalized epilepsies have temperature-dependent trafficking deficiencies. J Neurosci. 2006;6:2590–7.

    Article  Google Scholar 

  • Kaupmann K, Malitschek B, Schuler V. GABA(B)-receptor subtypes assemble into functional heteromeric complexes. Nature. 1998;396:683–7.

    Article  CAS  PubMed  Google Scholar 

  • Kaupmann K, Cryan JF, Wellendorph P, Mombereau C, Sansig G, Klebs K, et al. Specifi c gamma-hydroxybutyrate-binding sites but loss of pharmacological effects of gamma-hydroxybutyrate in GABA(B)(1)- deficient mice. Eur J Neurosci. 2003;18:2722–30.

    Article  PubMed  Google Scholar 

  • Kipnis PA, Sullivan BJ, Carter BM, Kadam SD. TrkB agonists prevent postischemic emergence of refractory neonatal seizures in mice. JCI Insight. 2020;5(12):e136007. https://doi.org/10.1172/jci.insight.13600.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kirkness EF, Fraser CM. A strong promoter element is located between alternative exons of a gene encoding the human gamma-aminobutyric acid-type A receptor beta 3 subunit (GABRB3). J Biol Chem. 1993;268(6):4420–8.

    Article  CAS  PubMed  Google Scholar 

  • Klitgaard H, Matagne A, Grimee R, Vanneste-Goemaere J, Margineanu DG. Electrophysiological, neurochemical and regional effects of levetiracetam in the rat pilocarpine model of temporal lobe epilepsy. Seizure. 2003;12:92–100.

    Article  PubMed  Google Scholar 

  • Kodera H, Ohba C, Kato M, Maeda T, Araki K, et al. De novo GABRA1 mutations in Ohtahara and West syndromes. Epilepsia. 2016;57:566–73.

    Article  CAS  PubMed  Google Scholar 

  • Korpi ER, Gründer G, Lüddens H. Drug interactions at GABAA receptors. Prog Neurobiol. 2002;67:113–59.

    Article  CAS  PubMed  Google Scholar 

  • Kwan P, Schachter SC, Brodie MJ. Drug-resistant epilepsy. N Engl J Med. 2011;365(10):919–26. https://doi.org/10.1056/NEJMra1004418.

    Article  CAS  PubMed  Google Scholar 

  • Joshi S, Rajasekaran K, Kapur J. GABAergic transmission in temporal lobe epilepsy: the role of neurosteroids. Exp Neurol. 2013;244:36–42. https://doi.org/10.1016/j.expneurol.2011.10.028.

  • Lachance-Touchette P, Brown P, Meloche C, Kinirons P, Lapointe L, et al. Novel α1 and γ2 GABAA receptor subunit mutations in families with idiopathic generalized epilepsy. Eur J Neurosci. 2011;34:237–49.

    Article  PubMed  Google Scholar 

  • Lam DM, Fei J, Zhang XY, Tam AC, Zhu LH, et al. Molecular cloning and structure of the human (GABATHG) GABA transporter gene. Brain Res Mol Brain Res. 1993;19:227–32.

    Article  CAS  PubMed  Google Scholar 

  • Lambert JJ, Belelli D, Peden DR, Vardy AW, Peters JA. Neurosteroid modulation of GABAA receptors. Prog Neurobiol. 2003;71:67–80.

    Article  CAS  PubMed  Google Scholar 

  • Lappalainen J, Tsai J, Amerine W, et al. Double-blind, randomized, placebo-controlled phase 3 trial to determine the efficacy and safety of ganaxolone as adjunctive therapy for adults with drug resistant focal-onset seizure. Neurology. 2017;88(16 Supplement):P5–237.

    Google Scholar 

  • Laschet JJ, Kurcewicz I, Minier F, Trottier S, Khallov-Laschet J, Louvel J, et al. Dysfunction of GABAA receptor glycolysis-dependent modulation in human partial epilepsy. Proc Natl Acad Sci U S A. 2007;104:3472–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laxer K, Blum D, Abou-Khalil BW, et al. Assessment of ganaxolone’s anticonvulsant activity using a randomized, double-blind, presurgical trial design. Ganaxolone Presurgical Study Group. Epilepsia. 2000;41(9):1187–94.

    Article  CAS  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;111:351e363.

    Article  Google Scholar 

  • Leidenheimer NJ. Regulation of excitation by GABA(A) receptor internalization. Results Probl Cell Differ. 2008;44:1–28.

    Article  CAS  PubMed  Google Scholar 

  • Lenzen KP, Heils A, Lorenz S, Hempelman A, Sander T. Association analysis of the arg220-to-his variation of the human gene encoding the GABA delta subunit with idiopathic generalized epilepsy. Epilepsy Res. 2005;65:53–7.

    Article  CAS  PubMed  Google Scholar 

  • Li RW, Yu W, Christie S, Miralles CP, Bai J, Loturco JJ, et al. Disruption of postsynaptic GABA receptor clusters leads to decreased GABAergic innervation of pyramidal neurons. J Neurochem. 2005;95:756–70.

    Article  CAS  PubMed  Google Scholar 

  • Li X, Zhou J, Chen Z, Chen S, Zhu F, Zhou L. Long-term expressional changes of Na+ -K+ -Cl− co-transporter 1 (NKCC1) and K+ −Cl− co-transporter 2 (KCC2) in CA1 region of hippocampus following lithium-pilocarpine induced status epilepticus (PISE) Brain research. 2008;1221:141–146. https://doi.org/10.1016/j.brainres.2008.04.047

  • Li X, Guo Q, Zheng Z, Wang X, Liu S. Immune-mediated epilepsy with GAD65 antibodies. J Neuroimmunol. 2020;15(341):577189. https://doi.org/10.1016/j.jneuroim.2020.577189.

    Article  CAS  Google Scholar 

  • Lim WM, Chin E, Tang BL, Chen T, Goh E. WNK3 maintains the GABAergic inhibitory tone, synaptic excitation and neuronal excitability via regulation of KCC2 cotransporter in mature neurons. Front Mol Neurosci. 2021;14:762142. https://doi.org/10.3389/fnmol.2021.762142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu R, Wang J, Liang S, Zhang G, Yang X. Role of NKCC1 and KCC2 in epilepsy: from expression to function. Front Neurol. 2020;17(10):1407. https://doi.org/10.3389/fneur.2019.01407.

    Article  Google Scholar 

  • Löscher W. Single-target versus multi-target drugs versus combinations of drugs with multiple targets: preclinical and clinical evidence for the treatment or prevention of epilepsy. Front Pharmacol. 2021;12:2894.

    Article  Google Scholar 

  • Löscher W, Puskarjov M, Kaila K. Cation-chloride cotransporters NKCC1 and KCC2 as potential targets for novel antiepileptic and antiepileptogenic treatments. Neuropharmacology. 2013;69:62–74. https://doi.org/10.1016/j.neuropharm.2012.05.045

  • Löscher W, Potschka H, Sisodiya SM, Vezzani A. Drug resistance in epilepsy: clinical impact, potential mechanisms, and new innovative treatment options. Pharmacol Rev. 2020;72(3):606–38. https://doi.org/10.1124/pr.120.019539.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Loup F, Wieser HG, Yonekawa Y, Aguzzi A, Fritschy JM. Selective alterations in GABAA receptor subtypes in human temporal lobe epilepsy. J Neurosci. 2000;20(14):5401–19. https://doi.org/10.1523/JNEUROSCI.20-14-05401.2000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lund IV, Hu Y, Raol YH, Benham RS, Faris R, Russek SJ, et al. BDNF selectively regulates GABA A receptor transcription by activation of the JAK/STAT pathway. Sci Signal. 2008;1(41):ra9.

    Article  PubMed  PubMed Central  Google Scholar 

  • Maa E, Bainbridge J, Spitz MC, Staley KJ. Oral bumetanide add-on therapy in refractory temporal lobe epilepsy. Epilepsia. 2007;48(Suppl 6) [abstract # 3.222]

    Google Scholar 

  • Maa EH, Kahle KT, Walcott BP, Spitz MC, Staley KJ. Diuretics and epilepsy: will the past and present meet? Epilepsia. 2011;52:1559–69. https://doi.org/10.1111/j.1528-1167.2011.03203.x.

    Article  CAS  PubMed  Google Scholar 

  • Macdonald RL, Kang JQ, Gallagher MJ. Mutations in GABAA receptor subunits associated with genetic epilepsies. J Physiol. 2010;588:1861–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maljevic S, Krampfl K, Cobilanschi J, Filgen N, Beyer S, Weber YG, et al. A mutation in the GABA-A receptor alpha-1-subunit is associated with absence epilepsy. Ann Neurol. 2006;59:983–7.

    Article  CAS  PubMed  Google Scholar 

  • Maljevic S, Keren B, Aung YH, Forster IC, Mignot C, et al. Novel GABRA2 variants in epileptic encephalopathy and intellectual disability with seizures. Brain. 2019;142:e15.

    Article  PubMed  Google Scholar 

  • Manent JB, Jorquera I, Ben Ari Y, Aniksztejn L, Represa A. Glutamate acting on AMPA but not NMDA receptors modulates the migration of hippocampal interneurons. J Neurosci. 2006;26:5901–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marsden KC, Beattie JB, Friedenthal J, Carroll RC. NMDA receptor activation potentiates inhibitory transmission through GABA receptor-associated protein-dependent exocytosis of GABA(A) receptors. J Neurosci. 2007;27(52):14326–37. https://doi.org/10.1523/JNEUROSCI.4433-07.2007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marshall FH, Jones KA, Kaupmann K, Bettler B. GABAB receptors—the fi rst 7TM heterodimers. Trends Pharmacol Sci. 1999;20:396–9.

    Article  CAS  PubMed  Google Scholar 

  • Mathern GW, Mendoza D, Lozada A, Pretorius JK, Danbolt NV, Nelson N, et al. Hippocampal GABA and glutamate transporter immunoreactivity in patients with temporal lobe epilepsy. Neurology. 1999;52:453e–72e.

    Article  Google Scholar 

  • Mathern GW, Adelson PD, Cahan LD, Leite JP. Hippocampal neuron damage in human epilepsy. Meyer’s hypothesis revisited. Prog Brain Res. 2002;135:237–51.

    Article  PubMed  Google Scholar 

  • Mazarati A, Shin D, Sankar R. Bumetanide inhibits rapid kindling in neonatal rats. Epilepsia. 2009;50(9):2117–22. https://doi.org/10.1111/j.1528-1167.2009.02048.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McKernan RM, Whiting PJ. Which GABAA receptor subtypes really occur in the brain? Trends Neurosci. 1996;19:139–43.

    Article  CAS  PubMed  Google Scholar 

  • McKinley DD, Lennon DJ, Carter DB. Cloning, sequence analysis and expression of two forms of mRNA coding for the human beta 2 subunit of the GABAA receptor. Brain Res Mol Brain Res. 1995;28:175–9.

    Article  CAS  PubMed  Google Scholar 

  • Mele M, Costa RO, Duarte CB. Alterations in GABAA-Receptor Trafficking and Synaptic Dysfunction in Brain Disorders. Front Cell Neurosci. 2019;13:77. https://doi.org/10.3389/fncel.2019.00077.

  • Mercado A, Mount DB, Gamba G. Electroneutral cation-chloride cotransporters in the central nervous system. Neurochem Res. 2004;29:17–25.

    Article  CAS  PubMed  Google Scholar 

  • Mihalek RM, Banerjee PK, Korpi ER, et al. Attenuated sensitivity to neuroactive steroids in gamma-aminobutyrate type A receptor delta subunit knockout mice. Proc Natl Acad Sci U S A. 1999;96:12905–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mihalek RM, Bowers BJ, Wehner JM, Kralic JE, VanDoren MJ, Morrow AL, Homanics GE. GABA(A)-receptor delta subunit knockout mice have multiple defects in behavioral responses to ethanol. Alcohol Clin Exp Res. 2001;25:1708–18.

    CAS  PubMed  Google Scholar 

  • Muñoz A, Mendez P, DeFelipe J, Alvarez-Leefmans FJ. Cation-chloride cotransporters and GABA-ergic innervation in the human epileptic hippocampus. Epilepsia. 2007;48:663–73.

    Article  PubMed  Google Scholar 

  • Najm I, Lal D, Alonso Vanegas M, Cendes F, Lopes-Cendes I, Palmini A, Paglioli E, Sarna HB, Walsh CA, Wiebe S, et al. The ILAE consensus classification of focal cortical dysplasia: an update proposed by an ad hoc task force of the ILAE diagnostic methods commission. Epilepsia. 2022;63(8):1899–919. https://doi.org/10.1111/epi.17301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nishimura T, Schwarzer C, Gasser E, Kato N, Vezzani A, Sperk G. Altered expression of GABA(A) and GABA(B) receptor subunit mRNAs in the hippocampus after kindling and electrically induced status epilepticus. Neuroscience. 2005;134:691–704.

    Article  CAS  PubMed  Google Scholar 

  • Ogris W, Poltl A, Hauer B, Ernst M, Oberto A, Wulff P, et al. Affi nity of various benzodiazepine site ligands in mice with a point mutation in the GABAA receptor γ2 subunit. Biochem Pharmacol. 2004;68:1621–9.

    Article  CAS  PubMed  Google Scholar 

  • Olafuyi O, Kapusta K, Reed A, Kolodziejczyk W, Saloni J, Hill GA. Investigation of cannabidiol’s potential targets in limbic seizures. In-silico approach. J Biomol Struct Dyn. 2022;21:1–13. https://doi.org/10.1080/07391102.2022.2124454.

    Article  CAS  Google Scholar 

  • Olsen RW. GABAA receptor: positive and negative allosteric modulators. Neuropharmacology. 2018;136(Pt A):10–22. https://doi.org/10.1016/j.neuropharm.2018.01.036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Olsen RW, Sieghart W. International Union of Pharmacology. LXX. Subtypes of gammaaminobutyric acid (A) receptors: classification on the basis of subunit composition, pharmacology, and function. Update. Pharmacol Rev. 2008;60:243–60.

    Article  CAS  PubMed  Google Scholar 

  • Orenstein N, Goldberg-Stern H, Straussberg R, Bazak L, Weisz Hubshman M, et al. A de novo GABRA2 missense mutation in severe early-onset epileptic encephalopathy with a choreiform movement disorder. Eur J Paediatr Neurol. 2018;22:516–24.

    Article  PubMed  Google Scholar 

  • Paolino MC, Ferretti A, Papetti L, et al. Cannabidiol as potential treatment in refractory pediatric epilepsy. Expert Rev Neurother. 2016;16(1):17–21.

    Article  CAS  PubMed  Google Scholar 

  • Pavlov I, Savtchenko LP, Kullmann DM, Semyanov A, Walker MC. Outwardly rectifying tonically active GABAA receptors in pyramidal cells modulate neuronal offset, not gain. J Neurosci. 2009;29:15341–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Payne JA, Stevenson TJ, Donaldson LF. Molecular characterization of a putative K-Cl cotransporter in rat brain. A neuronal-specifi c isoform. J Biol Chem. 1996;271:16245–52.

    Article  CAS  PubMed  Google Scholar 

  • Peng Z, Huang CS, Stell BM, Mody I, Houser CR. Altered expression of the d subunit of the GABA A receptor in a mouse model of temporal lobe epilepsy. J Neurosci. 2004;24:8629–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pirker S, Schwarzer C, Czech T, Baungartner C, Pockberg H, Maier H, et al. Increased expression of GABA A receptor β-subunits in the hippocampus of patients with temporal lobe epilepsy. J Neuropathol Exp Neurol. 2003;62:820–34.

    Article  CAS  PubMed  Google Scholar 

  • Pozzi D, Rasile M, Corradini I, Matteoli M. Environmental regulation of the chloride transporter KCC2: switching inflammation off to switch the GABA on? Transl Psychiatry. 2020;10:349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pressler R, Auvin S. Comparison of brain maturation among species: an example in translational research suggesting the possible use of bumetanide in newborn. Front Neurol. 2013;4:36. https://doi.org/10.3389/fneur.2013.00036.

  • Pressler RM, Boylan G, Marlow N, Blennow M, Chiron C, et al. Bumetanide for the treatment of seizures in newborn babies with hypoxic ischaemic encephalopathy (NEMO): an open-label, dose finding, and feasibility phase 1/2 trial. Lancet Neurol. 2015;14:469–77. https://doi.org/10.1016/S1474-4422(14)70303-5.

    Article  CAS  PubMed  Google Scholar 

  • Puskarjov M, Kahle KT, Ruusuvuori E, et al. Pharmacotherapeutic targeting of cation-chloride cotransporters in neonatal seizures. Epilepsia. 2014;55(6):806–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reddy DS. Neurosteroids: endogenous role in the human brain and therapeutic potentials. Prog Brain Res. 2010;186:113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reddy DS. Role of anticonvulsant and antiepileptogenic neurosteroids in the pathophysiology and treatment of epilepsy. Front Endocrinol (Lausanne). 2011;2(38):1–11.

    Google Scholar 

  • Reddy DS, Rogawski MA. Neurosteroids endogenous regulators of seizure susceptibility and role in the treatment of epilepsy. In: Noebels JL, Avoli M, Rogawski MA, et al., editors. Jasper’s basic mechanisms of the epilepsies. 4th ed. Oxford: Oxford University Press; 2012. p. 984–1002.

    Chapter  Google Scholar 

  • Reddy DS, Woodward R. Ganaxolone: a prospective overview. Drugs Future. 2004;29:227–42.

    Article  CAS  Google Scholar 

  • Reddy DS, Carver CM, Clossen B, Wu X. Extrasynaptic γ-aminobutyric acid type a receptor-mediated sex differences in the antiseizure activity of neurosteroids in status epilepticus and complex partial seizures. Epilepsia. 2019;60(4):730–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Remy S, Beck H. Molecular and cellular mechanisms of pharmacoresistance in epilepsy. Brain. 2006;129:18–35.

    Article  PubMed  Google Scholar 

  • Ritter DM, Holland K. Genetic testing in epilepsy. Semin Neurol. 2020;40:730–8.

    Article  PubMed  Google Scholar 

  • Rivera C, Voipio J, Payne JA, Rusuvuori E, Lahtinen H, Lamsa K, et al. The K+ /Cl− co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature. 1999;397:251–5.

    Article  CAS  PubMed  Google Scholar 

  • Rivera C, Li H, Thomas-Crusells J, Lahtinen H, Viitanen T, Nanobashuili A, et al. BDNF-induced TrkB activation down-regulates the K+ Cl− cotransporter KCC2 and impairs neuronal Cl − extrusion. J Cell Biol. 2002;159:747–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rogawski MA, Löscher W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci. 2004;5:553–64.

    Article  CAS  PubMed  Google Scholar 

  • Rogawski MA, Loya CM, Reddy K, et al. Neuroactive steroids for the treatment of status epilepticus. Epilepsia. 2013;54:93–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rogawski MA, Löscher W, Rho JM. Mechanisms of action of antiseizure drugs and the ketogenic diet. Cold Spring Harb Perspect Med. 2016;6:a022780.

    Article  PubMed  PubMed Central  Google Scholar 

  • Rosenthal ES, Claassen J, Wainwright MS, Husain AM, Vaitkevicius H, Raines S, Hoffmann E, Colquhoun H, Doherty JJ, Kanes SJ. Brexanolone as adjunctive therapy in super-refractory status epilepticus. Ann Neurol. 2017;82:342–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ruffolo G, Iyer A, Cifelli P, Roseti C, Mühlebner A, van Scheppingen J, Scholl T, Hainfellner JA, Feucht M, Krsek P, et al. Functional aspects of early brain development are preserved in tuberous sclerosis complex (TSC) epileptogenic lesions. Neurobiol Dis. 2016;95:93–101.

    Article  CAS  PubMed  Google Scholar 

  • Ruffolo G, Cifelli P, Roseti C, Thom M, van Vliet EA, Limatola C, Aronica E, Palma E. A novel GABAergic dysfunction in human Dravet syndrome. Epilepsia. 2018;59:2106–17.

    Article  CAS  PubMed  Google Scholar 

  • Ruffolo G, Cifelli P, Miranda-Lourenço C, De Felice E, Limatola C, Sebastião AM, Diógenes MJ, Aronica E, Palma E. Rare diseases of neurodevelopment: maintain the mystery or use a dazzling tool for investigation? The case of Rett syndrome. Neuroscience. 2019;439:146–52.

    Article  PubMed  Google Scholar 

  • Schijns O, Karaca Ü, Andrade P, de Nijs L, Küsters B, Peeters A, Dings J, Pannek H, Ebner A, Rijkers K, Hoogland G. Hippocampal GABA transporter distribution in patients with temporal lobe epilepsy and hippocampal sclerosis. J Chem Neuroanat. 2015;68:39–44. https://doi.org/10.1016/j.jchemneu.2015.07.004.

    Article  CAS  PubMed  Google Scholar 

  • Schipper S, Aalbers MW, Rijkers K, Swijsen A, Rigo JM, Hoogland G, Vles JS. Tonic GABAA receptors as potential target for the treatment of temporal lobe epilepsy. Mol Neurobiol. 2016;53(8):5252–65. https://doi.org/10.1007/s12035-015-9423-8.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Schwarzer C, Tsunashima K, Wanzenböck C, Fuchs K, Sieghart W, Sperk G. GABA A receptor subunits in the rat hippocampus II: altered distribution in kainic acid-induced temporal lobe epilepsy. Neuroscience. 1997;80:1001–17.

    Article  CAS  PubMed  Google Scholar 

  • Scimemi A, Semyanov A, Sperk G, Kullmann DM, Walker MC. Multiple and plastic receptors mediate tonic GABAA receptor currents in the hippocampus. J Neurosci. 2005;25:10016–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shen L, Cui WY, Chen RZ, Wang H. Differential modulation of GABAA and NMDA receptors by α7-nicotinic receptor desensitization in cultured rat hippocampal neurons. Acta Pharmacol Sin. 2016;37(3):312–21. https://doi.org/10.1038/aps.2015.106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shi YW, Zhang Q, Cai K, Poliquin S, Shen W, Winters N, Yi YH, Wang J, Hu N, Macdonald RL, Liao WP, Kang JQ. Synaptic clustering differences due to different GABRB3 mutations cause variable epilepsy syndromes. Brain J Neurol. 2019;142(10):3028–44. https://doi.org/10.1093/brain/awz250.

    Article  Google Scholar 

  • Sieghart W. Structure and pharmacology of γ-aminobutyric acid A receptor subtypes. Pharmacol Rev. 1995;47:181–234.

    CAS  PubMed  Google Scholar 

  • Sivakumaran S, Maguire J. Bumetanide reduces seizure progression and the development of pharmacoresistant status epilepticus. Epilepsia. 2016;57(2):222–32. https://doi.org/10.1111/epi.13270.

    Article  CAS  PubMed  Google Scholar 

  • Soghomonian JJ, Martin DL. Two isoforms of glutamate decarboxylase: why? Trends Pharmacol Sci. 1998;19:500–5.

    Article  CAS  PubMed  Google Scholar 

  • Sommer B, Poustka A, Spurr NK, Seeburg PH, et al. The murine GABAA receptor delta-subunit gene: structure and assignment to human chromosome 1. DNA Cell Biol. 1990;9:561–8.

    Article  CAS  PubMed  Google Scholar 

  • Sperk G, Drexel M, Pirker S. Neuronal plasticity in animal models and the epileptic human hippocampus. Epilepsia. 2009;50:29–31.

    Article  PubMed  PubMed Central  Google Scholar 

  • Staley KJ. Diuretics as antiepileptic drugs: should we go with the flow? Epilepsy Curr. 2002;2:35–8. https://doi.org/10.1046/j.1535-7597.2002.00018.x.

    Article  PubMed  PubMed Central  Google Scholar 

  • Stell BM, Brickley SG, Tang CY, Farrant M, Mody I. Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by delta subunit-containing GABAA receptors. Proc Natl Acad Sci U S A. 2003;100:14439–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Steudle F, Rehman S, Bampali K, Simeone X, Rona Z, et al. A novel de novo variant of GABRA1 causes increased sensitivity for GABA in vitro. Sci Rep. 2020;10:2379.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Talos DM, Sun H, Kosaras B, Joseph A, Folkerth RD, Poduri A, Madsen JR, Black PM, Jensen FE. Altered inhibition in tuberous sclerosis and type IIb cortical dysplasia. Ann Neurol. 2012;71:539–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tanaka M, Olsen RW, Medina MT, Schwartz E, Alonso ME, Duron RM, et al. Hyperglycosylation and reduced GABA currents of mutated GABRB3 polypeptide in remitting childhood absence epilepsy. Am J Hum Genet. 2008;82:1249–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tang X, Kim J, Zhou L, Wengert E, Zhang L, Wu Z, Carromeu C, Muotri AR, Marchetto MCN, Gage FH, et al. KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome. Proc Natl Acad Sci U S A. 2016;113:751–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tang F, Hartz AMS, Bauer BB. Drug-resistant epilepsy: multiple hypotheses, few answers. Front Neurol. 2017;8:301.

    Article  PubMed  PubMed Central  Google Scholar 

  • Tapia R. Biochemical pharmacology of GABA in CNS. In: Iversen LL, Iversen SD, Snyder SH, editors. Handbook of psychopharmacology. New York: Plenum Publishing Corporation; 1975.

    Google Scholar 

  • Turkmen S, Backstrom T, Wahlstrom G, et al. Tolerance to allopregnanolone with focus on the GABA-A receptor. Br J Pharmacol. 2011;162(2):311–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ulrich D, Bettler B. GABA(B) receptors: synaptic functions and mechanisms of diversity. Curr Opin Neurobiol. 2007;17:298–303.

    Article  CAS  PubMed  Google Scholar 

  • Urak L, Feucht M, Fathi N, Hornik K, Fuchs K, et al. A GABRB3 promoter haplotype associated with childhood absence epilepsy impairs transcriptional activity. Hum Mol Genet. 2006;15:2533–41.

    Article  CAS  PubMed  Google Scholar 

  • Uwera J, Nedergaard S, Andreasen M. A novel mechanism for the anticonvulsant effect of furosemide in rat hippocampus in vitro. Brain Res. 2015;1625:1–8. https://doi.org/10.1016/j.brainres.2015.08.014.

    Article  CAS  PubMed  Google Scholar 

  • Vanhatalo S, Hellstrom-Westas L, De Vries LS. Bumetanide for neonatal seizures: based on evidence or enthusiasm? Epilepsia. 2009;50:1292–3. https://doi.org/10.1111/j.1528-1167.2008.01894.x.

    Article  PubMed  Google Scholar 

  • Walls AB, Nilsen LH, Eyjolfsson EM, et al. GAD65 is essential for synthesis of GABA destined for tonic inhibition regulating epileptiform activity. J Neurochem. 2010;115:1398–408.

    Article  CAS  PubMed  Google Scholar 

  • Walls AB, Eyjolfsson EM, Smeland OB, Vestergaard HT, Hansen SL, Schousboe, et al. Knockout of GAD65 has major impact on synaptic GABA synthesized from astrocyte-derived glutamine. J Cereb Blood Flow Metab. 2011;31:494–503.

    Article  CAS  PubMed  Google Scholar 

  • Wang XJ, Buzsaki G. Gamma oscillation by synaptic inhibition in hippocampal interneuronal network model. J Neurosci. 1996;16:6402–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang DD, Kriegstein AR. Blocking early GABA depolarization with bumetanide results in permanent alterations in cortical circuits and sensorimotor gating deficits. Cereb Cortex. 2010;21:574–87.

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang X, Sun W, Zhu X, Li L, Wu X, Lin H, et al. Association between the gamma-aminobutyric acid type B receptor 1 and 2 gene polymorphisms and mesial temporal lobe epilepsy in a Han Chinese population. Epilepsy Res. 2008;81:198–203.

    Article  CAS  PubMed  Google Scholar 

  • Watanabe M, Maemura K, Kanbara K, Tamayama T, Hayasaki H. GABA and GABA receptors in the central nervous system and other organs. In: Jeon KW, editor. A survey of cell biology. San Diego, CA: Academic; 2002.

    Google Scholar 

  • Wieland HA, Luddens H, Seeburg PH. A single histidine in GABA A receptors is essential for benzodiazepine agonist binding. J Biol Chem. 1992;267:1426–9.

    Article  CAS  PubMed  Google Scholar 

  • Wilcox AS, Warrington JA, Gardiner K, et al. Human chromosomal localization of genes encoding the gamma 1 and gamma 2 subunits of the gamma-aminobutyric acid receptor indicates that members of this gene family are often clustered in the genome. Proc Natl Acad Sci U S A. 1992;89:5857–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wingrove P, Hadingham K, Wafford K, Kemp JA, Ragan CI, et al. Cloning and expression of a cDNA encoding the human GABA-A receptor alpha 5 subunit. Biochem Soc Trans. 1992;20:18S.

    Article  CAS  PubMed  Google Scholar 

  • Wohlfarth KM, Bianchi MT, Macdonald RL. Enhanced neurosteroid potentiation of ternary GABAA receptors containing the δ subunit. J Neurosci. 2002;22:1541–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu X, Gangisetty O, Carver CM, Reddy DS. Estrous cycle regulation of extrasynaptic delta-containing GABA-A receptor plasticity and tonic inhibition in the hippocampus subfields. J Pharmacol Exp Ther. 2013;346:146–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoo Y, Jung J, Lee YN, Lee Y, Cho H, et al. GABBR2 mutations determine phenotype in rett syndrome and epileptic encephalopathy. Ann Neurol. 2017;82:466–78.

    Article  CAS  PubMed  Google Scholar 

  • Zhan RZ, Nadler JV. Enhanced tonic GABA current in normotopic and hilar ectopic dentate granule cells after pilocarpine-induced status epilepticus. J Neurophysiol. 2009;102:670–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang N, Wei W, Mody I, Houser CR. Altered localization of GABA a receptor subunits on dentate granule cell dendrites influences tonic and phasic inhibition in a mouse model of epilepsy. J Neurosci. 2007;27:7520–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Medical Research Unit in Neurological Diseases, National Medical Center “Siglo XXI”, IMSS, Hospital of Specialties, Mexico City, Mexico

    Sandra Orozco-Suárez & Iris Angélica Feria-Romero

  2. Departamento de Biología Celular y Molecular, Centro Universitario de Ciencias Biológicas y Agropecuarias (CUCBA), Universidad de Guadalajara, Zapopan, Jalisco, Mexico

    Mónica Elisa Ureña-Guerrero

  3. Pharmacobiology Department, Center for Research and Advanced Studies, México, Mexico

    Luisa L. Rocha

  4. International Center for Epilepsy Surgery, HMG-Coyocan, Mexico City, Mexico

    Mario A. Alonso-Vanegas

Authors
  1. Sandra Orozco-Suárez
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  2. Iris Angélica Feria-Romero
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  3. Mónica Elisa Ureña-Guerrero
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  4. Luisa L. Rocha
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  5. Mario A. Alonso-Vanegas
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Corresponding author

Correspondence to Sandra Orozco-Suárez .

Editor information

Editors and Affiliations

  1. Pharmacobiology Department, Center for Research and Advanced Studies, México, Mexico

    Luisa L. Rocha

  2. Institute for Research in Physiopathology and Clinical Biochemistry (INFIBIOC), School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina

    Alberto Lazarowski

  3. Department of Neurology and Neurosurgery, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, Brazil

    Esper A. Cavalheiro

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© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG

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Orozco-Suárez, S., Feria-Romero, I.A., Ureña-Guerrero, M.E., Rocha, L.L., Alonso-Vanegas, M.A. (2023). GABAergic Neurotransmission Abnormalities in Pharmacoresistant Epilepsy: Experimental and Human Studies. In: Rocha, L.L., Lazarowski, A., Cavalheiro, E.A. (eds) Pharmacoresistance in Epilepsy. Springer, Cham. https://doi.org/10.1007/978-3-031-36526-3_16

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