Preclinical insights into therapeutic targeting of KCC2 for disorders of neuronal hyperexcitability

References

• Stafstrom CE, Carmant L. Seizures and epilepsy: an overview for neuroscientists. Cold Spring Harb Perspect Med. 2015;5(6):a022426-a022426.
   PubMed Web of Science ®Google Scholar
• McCagh J, Fisk JE, Baker GA. Epilepsy, psychosocial and cognitive functioning. Epilepsy Res. 2009;86:1–14.
   PubMed Web of Science ®Google Scholar
• Devinsky O, Spruill T, Thurman D, et al. Recognizing and preventing epilepsy-related mortality: A call for action. Neurology. 2016;86:779–786.
   PubMed Web of Science ®Google Scholar
• van Rijckevorsel K. Cognitive problems related to epilepsy syndromes, especially malignant epilepsies. Seizure. 2006;15:227–234.
   PubMed Web of Science ®Google Scholar
• Begley CE, Famulari M, Annegers JF, et al. The cost of epilepsy in the United States: an estimate from population-based clinical and survey data. Epilepsia. 2000;41:342–351.
   PubMed Web of Science ®Google Scholar
• Yoon D, Frick KD, Carr DA, et al. Economic impact of epilepsy in the United States. Epilepsia. 2009;50:2186–2191.
   PubMed Web of Science ®Google Scholar
• Avoli M, Louvel J, Pumain R, et al. Cellular and molecular mechanisms of epilepsy in the human brain. Prog Neurobiol. 2005;77:166–200.
   PubMed Web of Science ®Google Scholar
• Biagini G, Rustichelli C, Curia G, et al. Neurosteroids and Epileptogenesis. J Neuroendocrinol. 2013;25:980–990.
   PubMed Web of Science ®Google Scholar
• Shorvon S, Luciano AL. Prognosis of chronic and newly diagnosed epilepsy: revisiting temporal aspects. Curr Opin Neurol. 2007;20:208–212.
   PubMed Web of Science ®Google Scholar
• Cascino GD. When drugs and surgery don’t work. Epilepsia. 2008;49(Suppl 9):79–84.
   PubMedGoogle Scholar
• Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342:314–319.
   PubMed Web of Science ®Google Scholar
• Chen Z, Brodie MJ, Liew D, et al. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal Cohort study. JAMA Neurol. 2018;75:279–286.
   PubMed Web of Science ®Google Scholar
• D’Antuono M, Köhling R, Ricalzone S, et al. Antiepileptic drugs abolish ictal but not interictal epileptiform discharges in vitro. Epilepsia. 2010;51:423–431.
   PubMed Web of Science ®Google Scholar
• Ney GC, Lantos G, Barr WB, et al. Cerebellar atrophy in patients with long-term phenytoin exposure and epilepsy. Arch Neurol. 1994;51:767–771.
   PubMedGoogle Scholar
• Perucca P, Carter J, Vahle V, et al. Adverse antiepileptic drug effects: toward a clinically and neurobiologically relevant taxonomy. Neurology. 2009;72:1223–1229.
   PubMed Web of Science ®Google Scholar
• Ben-Menachem E. Neurostimulation-past, present, and beyond. Epilepsy Curr. 2012;12:188–191.
   PubMed Web of Science ®Google Scholar
• Puskarjov M, Seja P, Heron SE, et al. A variant of KCC2 from patients with febrile seizures impairs neuronal Cl- extrusion and dendritic spine formation. EMBO Rep. 2014. DOI:10.1002/embr.201438749.
   PubMed Web of Science ®Google Scholar
• Kahle KT, Merner ND, Friedel P, et al. Genetically encoded impairment of neuronal KCC2 cotransporter function in human idiopathic generalized epilepsy. EMBO Rep. 2014;15:766–774.
   PubMed Web of Science ®Google Scholar
• Stödberg T, McTague A, Ruiz AJ, et al. Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures. Nat Commun. 2015;6:8038.
   PubMed Web of Science ®Google Scholar
• Saitsu H, Watanabe M, Akita T, et al. Impaired neuronal KCC2 function by biallelic SLC12A5 mutations in migrating focal seizures and severe developmental delay. Sci Rep. 2016;6:30072.
   PubMed Web of Science ®Google Scholar
• Saito T, Ishii A, Sugai K, et al. A de novo missense mutation in SLC12A5 found in a compound heterozygote patient with epilepsy of infancy with migrating focal seizures. Clin Genet. 2017;92:654–658.
   PubMed Web of Science ®Google Scholar
• Till A, Szalai R, Hegyi M, et al. [A rare form of ion channel gene mutation identified as underlying cause of generalized epilepsy]. Orv Hetil. 2019;160:835–838.
   PubMed Web of Science ®Google Scholar
• de Guzman P, Inaba Y, Biagini G, et al. Subiculum network excitability is increased in a rodent model of temporal lobe epilepsy. Hippocampus. 2006;16:843–860.
   PubMed Web of Science ®Google Scholar
• Moore YE, Deeb TZ, Chadchankar H, et al. Potentiating KCC2 activity is sufficient to limit the onset and severity of seizures. Proc Natl Acad Sci U S A. 2018;115:10166–10171.
   PubMed Web of Science ®Google Scholar
• Moore YE, Kelley MR, Brandon NJ, et al. Seizing control of KCC2: a new therapeutic target for epilepsy. Trends Neurosci. 2017;40:555–571.
   PubMed Web of Science ®Google Scholar
• Kahle KT, Khanna AR, Duan J, et al. The KCC2 cotransporter and human epilepsy: getting excited about inhibition. Neuroscientist. 2016;22:555–562.
   PubMed Web of Science ®Google Scholar
• Di Cristo G, Awad PN, Hamidi S, et al. KCC2, epileptiform synchronization, and epileptic disorders. Prog Neurobiol. 2018;162:1–16.
   PubMed Web of Science ®Google Scholar
• Chamma I, Chevy Q, Poncer JC, et al. Role of the neuronal K-Cl co-transporter KCC2 in inhibitory and excitatory neurotransmission. Front Cell Neurosci. 2012;6:5.
   PubMed Web of Science ®Google Scholar
• Liu R, Wang J, Liang S, et al. Role of NKCC1 and KCC2 in epilepsy: from expression to function. Front Neurol. 2020;10:1407.
   PubMed Web of Science ®Google Scholar
• Yamada J, Okabe A, Toyoda H, et al. Cl- uptake promoting depolarizing GABA actions in immature rat neocortical neurones is mediated by NKCC1. J Physiol. 2004;557:829–841.
   PubMed Web of Science ®Google Scholar
• Kahle KT, Delpire E. Kinase-KCC2 coupling: Cl- rheostasis, disease susceptibility, therapeutic target. J Neurophysiol. 2016;115:8–18.
   PubMed Web of Science ®Google Scholar
• Williams JR, Sharp JW, Kumari VG, et al. The neuron-specific K-Cl cotransporter, KCC2. Antibody development and initial characterization of the protein. J Biol Chem. 1999;274:12656–12664.
   PubMedGoogle Scholar
• Li H, Khirug S, Cai C, et al. KCC2 interacts with the dendritic cytoskeleton to promote spine development. Neuron. 2007;56:1019–1033.
   PubMed Web of Science ®Google Scholar
• Llano O, Smirnov S, Soni S, et al. KCC2 regulates actin dynamics in dendritic spines via interaction with β-PIX. J Cell Biol. 2015;209:671–686.
   PubMed Web of Science ®Google Scholar
• Mavrovic M, Uvarov P, Delpire E, et al. Loss of non-canonical KCC2 functions promotes developmental apoptosis of cortical projection neurons. EMBO Rep. 2020;21(4):e48880. PMID: 32064760.
   PubMedGoogle Scholar
• Khazipov R, Valeeva G, Khalilov I. Depolarizing GABA and developmental epilepsies. CNS Neurosci Ther. 2015;21:83–91.
   PubMed Web of Science ®Google Scholar
• Li H, Tornberg J, Kaila K, et al. Patterns of cation-chloride cotransporter expression during embryonic rodent CNS development. Eur J Neurosci. 2002;16:2358–2370.
   PubMed Web of Science ®Google Scholar
• Stein V, Hermans-Borgmeyer I, Jentsch TJ, et al. Expression of the KCl cotransporter KCC2 parallels neuronal maturation and the emergence of low intracellular chloride. J Comp Neurol. 2004;468:57–64.
   PubMed Web of Science ®Google Scholar
• Ben-Ari Y, Khalilov I, Kahle KT, et al. The GABA excitatory/inhibitory shift in brain maturation and neurological disorders. Neuroscientist. 2012;18:467–486.
   PubMed Web of Science ®Google Scholar
• Kaila K, Price TJ, Payne JA, et al. Cation-chloride cotransporters in neuronal development, plasticity and disease. Nat Rev Neurosci. 2014;15:637–654.
   PubMed Web of Science ®Google Scholar
• Rivera C, Voipio J, Payne JA, et al. The K+/Cl− co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature. 1999;397:251–255.
   PubMed Web of Science ®Google Scholar
• LoTurco JJ, Owens DF, Heath MJ, et al. GABA and glutamate depolarize cortical progenitor cells and inhibit DNA synthesis. Neuron. 1995;15:1287–1298.
   PubMed Web of Science ®Google Scholar
• Haydar TF, Wang F, Schwartz ML, et al. Differential modulation of proliferation in the neocortical ventricular and subventricular zones. J Neurosci. 2000;20:5764–5774.
   PubMed Web of Science ®Google Scholar
• Behar TN, Schaffner AE, Scott CA, et al. Differential response of cortical plate and ventricular zone cells to GABA as a migration stimulus. J Neurosci. 1998;18:6378–6387.
   PubMed Web of Science ®Google Scholar
• Maric D, Liu QY, Maric I, et al. GABA expression dominates neuronal lineage progression in the embryonic rat neocortex and facilitates neurite outgrowth via GABA(A) autoreceptor/Cl- channels. J Neurosci. 2001;21:2343–2360.
   PubMed Web of Science ®Google Scholar
• Cherubini E, Gaiarsa JL, Ben-Ari Y. GABA: an excitatory transmitter in early postnatal life. Trends Neurosci. 1991;14:515–519.
   PubMed Web of Science ®Google Scholar
• Owens DF, Kriegstein AR. Is there more to gaba than synaptic inhibition? Nat Rev Neurosci. 2002;3:715–727.
   PubMed Web of Science ®Google Scholar
• Watanabe M, Zhang J, Mansuri MS, et al. Developmentally regulated KCC2 phosphorylation is essential for dynamic GABA-mediated inhibition and survival. Sci Signal. 2019. DOI:10.1126/scisignal.aaw9315
   Web of Science ®Google Scholar
• Pisella LI, Gaiarsa J-L, Diabira D, et al. Impaired regulation of KCC2 phosphorylation leads to neuronal network dysfunction and neurodevelopmental pathology. Sci Signal. 2019. DOI:10.1126/scisignal.aay0300
   PubMed Web of Science ®Google Scholar
• Goutierre M, Al Awabdh S, Donneger F, et al. KCC2 regulates neuronal excitability and hippocampal activity via interaction with task-3 channels. Cell Rep. 2019;28:91–103.e7.
   PubMed Web of Science ®Google Scholar
• Tanis JE, Bellemer A, Moresco JJ, et al. The potassium chloride cotransporter KCC-2 coordinates development of inhibitory neurotransmission and synapse structure in Caenorhabditis elegans. J Neurosci. 2009;29:9943–9954.
   PubMed Web of Science ®Google Scholar
• Hubner CA, Stein V, Hermans-Borgmeyer I, et al. Disruption of KCC2 reveals an essential role of K-Cl cotransport already in early synaptic inhibition. Neuron. 2001;30:515–524.
   PubMed Web of Science ®Google Scholar
• Hekmat-Scafe DS, Lundy MY, Ranga R, et al. Mutations in the K+/Cl- cotransporter gene kazachoc (kcc) increase seizure susceptibility in Drosophila. J Neurosci. 2006;26:8943–8954.
   PubMed Web of Science ®Google Scholar
• Chen L, Wan L, Wu Z, et al. KCC2 downregulation facilitates epileptic seizures. Sci Rep. 2017;7:156.
   PubMed Web of Science ®Google Scholar
• Kelley MR, Cardarelli RA, Smalley JL, et al. Locally reducing KCC2 activity in the hippocampus is sufficient to induce temporal lobe epilepsy. EBioMedicine. 2018;32:62–71.
   PubMed Web of Science ®Google Scholar
• Calderon‐Garcidueñas AL, Mathon B, Lévy P, et al. New clinicopathological associations and histoprognostic markers in ILAE types of hippocampal sclerosis. Brain Pathol. 2018;28:644–655.
   PubMed Web of Science ®Google Scholar
• Huberfeld G, Wittner L, Clemenceau S, et al. Perturbed chloride homeostasis and GABAergic signaling in human temporal lobe epilepsy. J Neurosci. 2007;27:9866–9873.
   PubMed Web of Science ®Google Scholar
• Palma E, Amici M, Sobrero F, et al. Anomalous levels of Cl- transporters in the hippocampal subiculum from temporal lobe epilepsy patients make GABA excitatory. Proc Natl Acad Sci U S A. 2006;103:8465–8468.
   PubMed Web of Science ®Google Scholar
• Pallud J, Le Van Quyen M, Bielle F, et al. Cortical GABAergic excitation contributes to epileptic activities around human glioma. Sci Transl Med. 2014;6:244ra89.
   PubMed Web of Science ®Google Scholar
• Shimizu-Okabe C, Tanaka M, Matsuda K, et al. KCC2 was downregulated in small neurons localized in epileptogenic human focal cortical dysplasia. Epilepsy Res. 2011;93:177–184.
   PubMed Web of Science ®Google Scholar
• Kahle KT, Khanna A, Clapham DE, et al. Therapeutic restoration of spinal inhibition via druggable enhancement of potassium-chloride cotransporter KCC2-mediated chloride extrusion in peripheral neuropathic pain. JAMA Neurol. 2014;71:640–645.
   PubMed Web of Science ®Google Scholar
• Boulenguez P, Liabeuf S, Bos R, et al. Down-regulation of the potassium-chloride cotransporter KCC2 contributes to spasticity after spinal cord injury. Nat Med. 2010;16:302–307.
   PubMed Web of Science ®Google Scholar
• Hinz L, Torrella Barrufet J, Heine VM. KCC2 expression levels are reduced in post mortem brain tissue of Rett syndrome patients. Acta Neuropathol Commun. 2019;7:196.
   PubMed Web of Science ®Google Scholar
• Duy PQ, David WB, Kahle KT. Identification of KCC2 mutations in human epilepsy suggests strategies for therapeutic transporter modulation. Front Cell Neurosci. 2019;13:515.
   PubMed Web of Science ®Google Scholar
• Lee HHC, Deeb TZ, Walker JA, et al. NMDA receptor activity downregulates KCC2 resulting in depolarizing GABAA receptor-mediated currents. Nat Neurosci. 2011;14:736–743.
   PubMed Web of Science ®Google Scholar
• Schevon CA, Weiss SA, McKhann G, et al. Evidence of an inhibitory restraint of seizure activity in humans. Nat Commun. 2012;3:1060.
   PubMed Web of Science ®Google Scholar
• Trevelyan AJ, Sussillo D, Watson BO, et al. Modular propagation of epileptiform activity: evidence for an inhibitory veto in neocortex. J Neurosci. 2006;26:12447–12455.
   PubMed Web of Science ®Google Scholar
• Cope DW, Di Giovanni G, Fyson SJ, et al. Enhanced tonic GABAA inhibition in typical absence epilepsy. Nat Med. 2009;15:1392–1398.
   PubMed Web of Science ®Google Scholar
• Tassinari CA, Dravet C, Roger J, et al. Tonic status epilepticus precipitated by intravenous benzodiazepine in five patients with Lennox-Gastaut syndrome. Epilepsia. 1972;13:421–435.
   PubMed Web of Science ®Google Scholar
• Hosford DA, Wang Y. Utility of the lethargic (lh/lh) mouse model of absence seizures in predicting the effects of lamotrigine, vigabatrin, tiagabine, gabapentin, and topiramate against human absence seizures. Epilepsia. 1997;38:408–414.
   PubMed Web of Science ®Google Scholar
• Klaassen A, Glykys J, Maguire J, et al. Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy. Proc Natl Acad Sci U S A. 2006;103:19152–19157.
   PubMed Web of Science ®Google Scholar
• Cohen I, Navarro V, Clemenceau S, et al. On the origin of interictal activity in human temporal lobe epilepsy in vitro. Science. 2002;298:1418–1421.
   PubMed Web of Science ®Google Scholar
• Magloire V, Cornford J, Lieb A, et al. KCC2 overexpression prevents the paradoxical seizure-promoting action of somatic inhibition. Nat Commun. 2019;10:1225.
   PubMed Web of Science ®Google Scholar
• Doyon N, Vinay L, Prescott SA, et al. Chloride regulation: a dynamic equilibrium crucial for synaptic inhibition. Neuron. 2016;89:1157–1172.
   PubMed Web of Science ®Google Scholar
• Ellender TJ, Raimondo JV, Irkle A, et al. Excitatory effects of parvalbumin-expressing interneurons maintain hippocampal epileptiform activity via synchronous afterdischarges. J Neurosci. 2014;34:15208–15222.
   PubMed Web of Science ®Google Scholar
• Fujiwara-Tsukamoto Y, Isomura Y, Nambu A, et al. Excitatory gaba input directly drives seizure-like rhythmic synchronization in mature hippocampal CA1 pyramidal cells. Neuroscience. 2003;119:265–275.
   PubMed Web of Science ®Google Scholar
• Puskarjov M, Ahmad F, Kaila K, et al. Activity-dependent cleavage of the K-Cl cotransporter KCC2 mediated by calcium-activated protease calpain. J Neurosci. 2012;32:11356–11364.
   PubMed Web of Science ®Google Scholar
• Chamma I, Heubl M, Chevy Q, et al. Activity-dependent regulation of the K/Cl transporter KCC2 membrane diffusion, clustering, and function in hippocampal neurons. J Neurosci. 2013;33:15488–15503.
   PubMed Web of Science ®Google Scholar
• Rinehart J, Maksimova YD, Tanis JE, et al. Sites of regulated phosphorylation that control K-Cl cotransporter activity. Cell. 2009;138:525–536.
   PubMed Web of Science ®Google Scholar
• Friedel P, Kahle KT, Zhang J, et al. WNK1-regulated inhibitory phosphorylation of the KCC2 cotransporter maintains the depolarizing action of GABA in immature neurons. Sci Signal. 2015;8:ra65.
   PubMed Web of Science ®Google Scholar
• Titz S, Sammler EM, Hormuzdi SG. Could tuning of the inhibitory tone involve graded changes in neuronal chloride transport? Neuropharmacology. 2015;95:321–331.
   PubMed Web of Science ®Google Scholar
• Heubl M, Zhang J, Pressey JC, et al. GABAA receptor dependent synaptic inhibition rapidly tunes KCC2 activity via the Cl(-)-sensitive WNK1 kinase. Nat Commun. 2017;8:1776.
   PubMed Web of Science ®Google Scholar
• Lee HHC, Walker JA, Williams JR, et al. Direct protein kinase C-dependent phosphorylation regulates the cell surface stability and activity of the potassium chloride cotransporter KCC2. J Biol Chem. 2007;282:29777–29784.
   PubMed Web of Science ®Google Scholar
• Raimondo JV, Dulla C. When a good cop turns bad: the pro-ictal action of parvalbumin expressing interneurons during seizures. Epilepsy Curr. 2019;19:256–257.
   PubMed Web of Science ®Google Scholar
• Gagnon M, Bergeron MJ, Lavertu G, et al. Chloride extrusion enhancers as novel therapeutics for neurological diseases. Nat Med. 2013;19:1524–1528.
   PubMed Web of Science ®Google Scholar
• Chen B, Li Y, Yu B, et al. Reactivation of dormant relay pathways in injured spinal cord by KCC2 manipulations. Cell. 2018;174:521–535.e13.
   PubMed Web of Science ®Google Scholar
• Cardarelli RA, Jones K, Pisella LI, et al. The small molecule CLP257 does not modify activity of the K+–Cl− co-transporter KCC2 but does potentiate GABAA receptor activity. Nat Med. 2017;23:1394–1396.
   PubMed Web of Science ®Google Scholar
• Liabeuf S, Stuhl-Gourmand L, Gackière F, et al. Prochlorperazine increases KCC2 function and reduces spasticity after spinal cord injury. J Neurotrauma. 2017;34:3397–3406.
   PubMed Web of Science ®Google Scholar
• Tang X, Drotar J, Li K, et al. Pharmacological enhancement of KCC2 gene expression exerts therapeutic effects on human Rett syndrome neurons and Mecp2 mutant mice. Sci Transl Med. 2019;11:eaau0164.
   PubMed Web of Science ®Google Scholar
• Alessi DR, Zhang J, Khanna A, et al. The WNK-SPAK/OSR1 pathway: master regulator of cation-chloride cotransporters. Sci Signal. 2014;7:re3.
   PubMed Web of Science ®Google Scholar
• Kahle KT, Schmouth J-F, Lavastre V, et al. Inhibition of the kinase WNK1/HSN2 ameliorates neuropathic pain by restoring GABA inhibition. Sci Signal. 2016;9:ra32.
   PubMed Web of Science ®Google Scholar
• Kahle KT, Rinehart J, de Los Heros P, et al. WNK3 modulates transport of Cl- in and out of cells: implications for control of cell volume and neuronal excitability. Proc Natl Acad Sci U S A. 2005;102:16783–16788.
   PubMed Web of Science ®Google Scholar
• Yamada K, Zhang J-H, Xie X, et al. Discovery and Characterization of Allosteric WNK Kinase Inhibitors. ACS Chem Biol. 2016;11:3338–3346.
   PubMed Web of Science ®Google Scholar
• Yamada K, Levell J, Yoon T, et al. Optimization of Allosteric With-No-Lysine (WNK) kinase inhibitors and efficacy in rodent hypertension models. J Med Chem. 2017;60:7099–7107.
   PubMed Web of Science ®Google Scholar
• Kikuchi E, Mori T, Zeniya M, et al. Discovery of novel SPAK inhibitors that block WNK kinase signaling to cation chloride transporters. J Am Soc Nephrol. 2015;26:1525–1536.
   PubMed Web of Science ®Google Scholar
• AlAmri MA, Kadri H, Alderwick LJ, et al. Rafoxanide and closantel inhibit SPAK and OSR1 kinases by binding to a highly conserved allosteric site on their C-terminal domains. ChemMedChem. 2017;12:639–645.
   PubMed Web of Science ®Google Scholar
• Mori T, Kikuchi E, Watanabe Y, et al. Chemical library screening for WNK signalling inhibitors using fluorescence correlation spectroscopy. Biochem J. 2013;455:339–345.
   PubMed Web of Science ®Google Scholar
• Bos R, Sadlaoud K, Boulenguez P, et al. Activation of 5-HT2A receptors upregulates the function of the neuronal K-Cl cotransporter KCC2. Proc Natl Acad Sci U S A. 2013;110:348–353.
   PubMed Web of Science ®Google Scholar
• Sánchez-Brualla I, Boulenguez P, Brocard C, et al. Activation of 5-HT2A receptors restores KCC2 function and reduces neuropathic pain after spinal cord injury. Neuroscience. 2018;387:48–57.
   PubMed Web of Science ®Google Scholar
• Kimmey BA, Ostroumov A, Dani JA. 5-HT2A receptor activation normalizes stress-induced dysregulation of GABAergic signaling in the ventral tegmental area. Proc Natl Acad Sci U S A. 2019. DOI:10.1073/pnas.1911446116
   PubMed Web of Science ®Google Scholar
• Baker GA, Jacoby A, Buck D, et al. Quality of life of people with epilepsy: a European study. Epilepsia. 1997;38:353–362.
   PubMed Web of Science ®Google Scholar
• Park S-P, Kwon S-H. Cognitive effects of antiepileptic drugs. J Clin Neurol. 2008;4:99–106.
   PubMed Web of Science ®Google Scholar
• Moore YE, Conway LC, Wobst HJ, et al. Developmental Regulation of KCC2 Phosphorylation Has Long-Term Impacts on Cognitive Function. Front Mol Neurosci. 2019;12:173.
   PubMed Web of Science ®Google Scholar
• Nakamura K, Moorhouse AJ, Cheung DL, et al. Overexpression of neuronal K+–Cl− co-transporter enhances dendritic spine plasticity and motor learning. J Physiol Sci. 2019;69:453–463.
   PubMed Web of Science ®Google Scholar
• Lowenstein DH. Seizures and Epilepsy. In: Longo DL, Fauci AS, Kasper DL, et al., editors. Harrison’s Princ. Intern. Med. 20th ed. New York: McGraw-Hill Education LLC; 2018. p. 3050–3068.
   Google Scholar
• Cornes SB, Griffin EA Jr., Lowenstein DH. Pharmacology of abnormal electrical neurotransmission in the central nervous system. In: Golan DE, Armstrong EJ, Armstrong AW, editors. Princ. Pharmacol. Pathophysiol. basis drug Ther., Fourth. Philadelphia: Wolters Kluwer Health; 2017. p. 249–264.
   Google Scholar
• Wang Y, Xu C, Xu Z, et al. Depolarized GABAergic signaling in subicular microcircuits mediates generalized seizure in temporal lobe epilepsy. Neuron. 2017;95:92–105.e5.
   PubMed Web of Science ®Google Scholar
• Knopp A, Frahm C, Fidzinski P, et al. Loss of GABAergic neurons in the subiculum and its functional implications in temporal lobe epilepsy. Brain. 2008;131:1516–1527.
   PubMed Web of Science ®Google Scholar
• Wong M. Too much inhibition leads to excitation in absence epilepsy. Epilepsy Curr. 2010;10:131–132.
   PubMed Web of Science ®Google Scholar
• Castilla-Guerra L, Fernández-Moreno M del C, López-Chozas JM, et al. Electrolytes disturbances and seizures. Epilepsia. 2006;47:1990–1998.
   PubMed Web of Science ®Google Scholar
• Beghi E, Carpio A, Forsgren L, et al. Recommendation for a definition of acute symptomatic seizure. Epilepsia. 2010;51:671–675.
   PubMed Web of Science ®Google Scholar
• Jessberger S, Parent JM. Epilepsy and adult neurogenesis. Cold Spring Harb Perspect Biol. 2015;7:a020677.
   PubMed Web of Science ®Google Scholar
• Rossi AR, Angelo MF, Villarreal A, et al. Gabapentin administration reduces reactive gliosis and neurodegeneration after pilocarpine-induced status epilepticus. PLoS One. 2013;8:e78516.
   PubMed Web of Science ®Google Scholar
• Fabene PF, Mora GN, Martinello M, et al. A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nat Med. 2008;14:1377–1383.
   PubMed Web of Science ®Google Scholar
• Duy PQ, Berberoglu MA, Beattie CE, et al. Cellular responses to recurrent pentylenetetrazole-induced seizures in the adult zebrafish brain. Neuroscience. 2017;349:118–127.
   PubMed Web of Science ®Google Scholar
• Curia G, Lucchi C, Vinet J, et al. Pathophysiogenesis of mesial temporal lobe epilepsy: is prevention of damage antiepileptogenic? Curr Med Chem. 2014;21:663–688.
   PubMed Web of Science ®Google Scholar