{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:25:35Z","timestamp":1790771135525,"version":"4.1.0"},"reference-count":141,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,1,31]],"date-time":"2023-01-31T00:00:00Z","timestamp":1675123200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Alzheimer\u2019s New Zealand","award":["3718869"],"award-info":[{"award-number":["3718869"]}]},{"name":"Alzheimer\u2019s New Zealand","award":["3719321"],"award-info":[{"award-number":["3719321"]}]},{"name":"Alzheimer\u2019s New Zealand","award":["501029"],"award-info":[{"award-number":["501029"]}]},{"name":"Alzheimer\u2019s New Zealand","award":["3720863"],"award-info":[{"award-number":["3720863"]}]},{"name":"Alzheimer\u2019s New Zealand","award":["3627373"],"award-info":[{"award-number":["3627373"]}]},{"name":"Freemasons New Zealand","award":["3718869"],"award-info":[{"award-number":["3718869"]}]},{"name":"Freemasons New Zealand","award":["3719321"],"award-info":[{"award-number":["3719321"]}]},{"name":"Freemasons New Zealand","award":["501029"],"award-info":[{"award-number":["501029"]}]},{"name":"Freemasons New Zealand","award":["3720863"],"award-info":[{"award-number":["3720863"]}]},{"name":"Freemasons New Zealand","award":["3627373"],"award-info":[{"award-number":["3627373"]}]},{"name":"Alzheimer\u2019s New Zealand Charitable Trust","award":["3718869"],"award-info":[{"award-number":["3718869"]}]},{"name":"Alzheimer\u2019s New Zealand Charitable Trust","award":["3719321"],"award-info":[{"award-number":["3719321"]}]},{"name":"Alzheimer\u2019s New Zealand Charitable Trust","award":["501029"],"award-info":[{"award-number":["501029"]}]},{"name":"Alzheimer\u2019s New Zealand Charitable Trust","award":["3720863"],"award-info":[{"award-number":["3720863"]}]},{"name":"Alzheimer\u2019s New Zealand Charitable Trust","award":["3627373"],"award-info":[{"award-number":["3627373"]}]},{"name":"Health Research Council of New Zealand","award":["3718869"],"award-info":[{"award-number":["3718869"]}]},{"name":"Health Research Council of New Zealand","award":["3719321"],"award-info":[{"award-number":["3719321"]}]},{"name":"Health Research Council of New Zealand","award":["501029"],"award-info":[{"award-number":["501029"]}]},{"name":"Health Research Council of New Zealand","award":["3720863"],"award-info":[{"award-number":["3720863"]}]},{"name":"Health Research Council of New Zealand","award":["3627373"],"award-info":[{"award-number":["3627373"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Neurological diseases including Alzheimer\u2019s, Huntington\u2019s disease, Parkinson\u2019s disease, Down syndrome and epilepsy, and neuropsychiatric disorders such as schizophrenia, are conditions that affect not only individuals but societies on a global scale. Current therapies offer a means for small symptomatic relief, but recently there has been increasing demand for therapeutic alternatives. The \u03b3-aminobutyric acid (GABA)ergic signaling system has been investigated for developing new therapies as it has been noted that any dysfunction or changes to this system can contribute to disease progression. Expression of the K-Cl-2 (KCC2) and N-K-C1-1 (NKCC1) cation-chloride cotransporters (CCCs) has recently been linked to the disruption of GABAergic activity by affecting the polarity of GABAA receptor signaling. KCC2 and NKCC1 play a part in multiple neurological and neuropsychiatric disorders, making them a target of interest for potential therapies. This review explores current research suggesting the pathophysiological role and therapeutic importance of KCC2 and NKCC1 in neuropsychiatric and neurological disorders.<\/jats:p>","DOI":"10.3390\/molecules28031344","type":"journal-article","created":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T01:36:59Z","timestamp":1675215419000},"page":"1344","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":58,"title":["Cation-Chloride Cotransporters KCC2 and NKCC1 as Therapeutic Targets in Neurological and Neuropsychiatric Disorders"],"prefix":"10.3390","volume":"28","author":[{"given":"Patricia","family":"Lam","sequence":"first","affiliation":[{"name":"Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Newland","sequence":"additional","affiliation":[{"name":"Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3385-9498","authenticated-orcid":false,"given":"Richard L. M.","family":"Faull","sequence":"additional","affiliation":[{"name":"Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3801-4956","authenticated-orcid":false,"given":"Andrea","family":"Kwakowsky","sequence":"additional","affiliation":[{"name":"Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand"},{"name":"Pharmacology and Therapeutics, School of Medicine, Galway Neuroscience Centre, University of Galway, H91 W5P7 Galway, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.neubiorev.2016.06.014","article-title":"Insights on the pathophysiology of Alzheimer\u2019s disease: The crosstalk between amyloid pathology, neuroinflammation and the peripheral immune system","volume":"68","author":"Ferreira","year":"2016","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_2","unstructured":"Alzheimers New Zealand Incorporated, and Deloitte (2012). Updated Dementia Economic Impact Report, 2011, New Zealand, Alzheimers NZ."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.1126\/science.1162844","article-title":"Clusters of Hyperactive Neurons near Amyloid Plaques in a Mouse Model of Alzheimer\u2019s Disease","volume":"321","author":"Busche","year":"2008","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.neuroscience.2017.03.041","article-title":"Impaired expression of GABA transporters in the human Alzheimer\u2019s disease hippocampus, subiculum, entorhinal cortex and superior temporal gyrus","volume":"351","author":"Fuhrer","year":"2017","journal-title":"Neuroscience"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/S0306-4522(00)00163-9","article-title":"Density and pharmacology of \u03b15 subunit-containing GABA A receptors are preserved in hippocampus of Alzheimer\u2019s disease patients","volume":"98","author":"Howell","year":"2000","journal-title":"Neuroscience"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1016\/j.stem.2009.10.015","article-title":"GABAergic Interneuron Dysfunction Impairs Hippocampal Neurogenesis in Adult Apolipoprotein E4 Knockin Mice","volume":"5","author":"Li","year":"2009","journal-title":"Cell Stem Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"258","DOI":"10.3389\/fnmol.2019.00258","article-title":"The Role of Microglia and Astrocytes in Huntington\u2019s Disease","volume":"12","author":"Palpagama","year":"2019","journal-title":"Front. Mol. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"E1618","DOI":"10.1073\/pnas.1716871115","article-title":"Restoring GABAergic inhibition rescues memory deficits in a Huntington\u2019s disease mouse model","volume":"115","author":"Dargaei","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"817013","DOI":"10.3389\/fncel.2021.817013","article-title":"Striatal Chloride Dysregulation and Impaired GABAergic Signaling Due to Cation-Chloride Cotransporter Dysfunction in Huntington\u2019s Disease","volume":"15","author":"Serranilla","year":"2022","journal-title":"Front. Cell. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1002\/ana.410170310","article-title":"Occurrence of neuropathological changes and dementia of Alzheimer\u2019s disease in Down\u2019s syndrome","volume":"17","author":"Wisniewski","year":"1985","journal-title":"Ann. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1038\/nm.3827","article-title":"Reversing excitatory GABAAR signaling restores synaptic plasticity and memory in a mouse model of Down syndrome","volume":"21","author":"Deidda","year":"2015","journal-title":"Nat. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s12929-015-0138-y","article-title":"Down syndrome: An insight of the disease","volume":"22","author":"Asim","year":"2015","journal-title":"J. Biomed. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1177\/0269881111405366","article-title":"Specific targeting of the GABA-A receptor \u03b15 subtype by a selective inverse agonist restores cognitive deficits in Down syndrome mice","volume":"25","author":"Braudeau","year":"2011","journal-title":"J. Psychopharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.neubiorev.2013.12.008","article-title":"Treating enhanced GABAergic inhibition in Down syndrome: Use of GABA \u03b15-selective inverse agonists","volume":"46","author":"Delatour","year":"2014","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7776","DOI":"10.1523\/JNEUROSCI.1527-09.2009","article-title":"Dopamine-Deprived Striatal GABAergic Interneurons Burst and Generate Repetitive Gigantic IPSCs in Medium Spiny Neurons","volume":"29","author":"Dehorter","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"18047","DOI":"10.1523\/JNEUROSCI.2474-12.2012","article-title":"Subthalamic lesion or levodopa treatment rescues giant GABAergic currents of PINK1-deficient striatum","volume":"32","author":"Dehorter","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1097\/WNF.0000000000000114","article-title":"Bumetanide to Treat Parkinson Disease: A Report of 4 Cases","volume":"39","author":"Damier","year":"2016","journal-title":"Clin. Neuropharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9866","DOI":"10.1523\/JNEUROSCI.2761-07.2007","article-title":"Perturbed Chloride Homeostasis and GABAergic Signaling in Human Temporal Lobe Epilepsy","volume":"27","author":"Huberfeld","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"11088","DOI":"10.1523\/JNEUROSCI.1234-11.2011","article-title":"Expression of GABA signaling molecules KCC2, NKCC1, and GAD1 in cortical development and schizophrenia","volume":"31","author":"Hyde","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1016\/j.tins.2017.07.001","article-title":"NKCC1Chloride Importer Antagonists Attenuate Many Neurological and Psychiatric Disorders","volume":"40","year":"2017","journal-title":"Trends Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/j.neuron.2015.06.017","article-title":"Altered Neuronal and Circuit Excitability in Fragile X Syndrome","volume":"87","author":"Contractor","year":"2015","journal-title":"Neuron"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/nature09582","article-title":"GABAergic dysfunction mediates autism-like stereotypies and Rett syndrome phenotypes","volume":"468","author":"Chao","year":"2010","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Govindpani, K., Guzm\u00e1n, B.C.-F., Vinnakota, C., Waldvogel, H.J., Faull, R.L., and Kwakowsky, A. (2017). Towards a better understanding of GABAergic remodeling in alzheimer\u2019s disease. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18081813"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1038\/ncpneuro0883","article-title":"Roles of the cation-chloride cotransporters in neurological disease","volume":"4","author":"Kahle","year":"2008","journal-title":"Nat. Clin. Pract. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1038\/nrn920","article-title":"Excitatory actions of gaba during development: The nature of the nurture","volume":"3","year":"2002","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1038\/229628a0","article-title":"Localizing 3H-GABA in nerve terminals of rat cerebral cortex by electron microscopic autoradiography","volume":"229","author":"Bloom","year":"1971","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1002\/ana.410200510","article-title":"A postmortem study of amino acid neurotransmitters in Alzheimer\u2019s disease","volume":"20","author":"Ellison","year":"1986","journal-title":"Ann. Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/0896-6273(91)90077-D","article-title":"Two genes encode distinct glutamate decarboxylases","volume":"7","author":"Erlander","year":"1991","journal-title":"Neuron"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1111\/j.1471-4159.1991.tb08211.x","article-title":"Two Forms of the \u03b3-Aminobutyric Acid Synthetic Enzyme Glutamate Decarboxylase Have Distinct Intraneuronal Distributions and Cofactor Interactions","volume":"56","author":"Kaufman","year":"1991","journal-title":"J. Neurochem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1002\/mus.1044","article-title":"Molecular mechanisms of neurotransmitter release","volume":"24","author":"Fon","year":"2001","journal-title":"Muscle Nerve"},{"key":"ref_31","first-page":"420","article-title":"Axo-somatic and axo-dendritic synapses of the cerebral cortex: An electron microscope study","volume":"93","author":"Gray","year":"1959","journal-title":"J. Anat."},{"key":"ref_32","first-page":"291","article-title":"International union of pharmacology. XV. Subtypes of \u03b3-aminobutyric acid(A) receptors: Classification on the basis of subunit structure and receptor function","volume":"50","author":"Barnard","year":"1998","journal-title":"Pharmacol. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6726","DOI":"10.1073\/pnas.89.15.6726","article-title":"5 subtypes of type-a gamma-aminobutyric-acid receptors identified in neurons by double and triple immunofluorescence staining with subunit-specific antibodies","volume":"89","author":"Fritschy","year":"1992","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/S0197-0186(99)00048-0","article-title":"The GABA-A receptor gene family: New targets for therapeutic intervention","volume":"34","author":"Whiting","year":"1999","journal-title":"Neurochem. Int."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1113\/jphysiol.1988.sp017390","article-title":"Two inhibitory postsynaptic potentials, and GABAA and GABAB receptor-mediated responses in neocortex of rat and cat","volume":"406","author":"Connors","year":"1988","journal-title":"J. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1152\/jn.1989.62.5.1018","article-title":"GABA as an inhibitory neurotransmitter in human cerebral cortex","volume":"62","author":"McCormick","year":"1989","journal-title":"J. Neurophysiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1152\/physrev.00011.2004","article-title":"Molecular Physiology and Pathophysiology of Electroneutral Cation-Chloride Cotransporters","volume":"85","author":"Gamba","year":"2005","journal-title":"Physiol. Rev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/S0169-328X(02)00190-0","article-title":"Molecular, functional, and genomic characterization of human KCC2, the neuronal K\u2013Cl cotransporter","volume":"103","author":"Song","year":"2002","journal-title":"Mol. Brain Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1038\/nrn3819","article-title":"Cation-chloride cotransporters in neuronal development, plasticity and disease","volume":"15","author":"Kaila","year":"2014","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1038\/nn.2806","article-title":"NMDA receptor activity downregulates KCC2 resulting in depolarizing GABAA receptor-mediated currents","volume":"14","author":"Lee","year":"2011","journal-title":"Nat. Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/16697","article-title":"The K + \/Cl \u2212 co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation","volume":"397","author":"Kaila","year":"1999","journal-title":"Nature"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3419","DOI":"10.1523\/JNEUROSCI.1377-08.2009","article-title":"NKCC1-Dependent GABAergic Excitation Drives Synaptic Network Maturation during Early Hippocampal Development","volume":"29","author":"Pfeffer","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.celrep.2016.03.013","article-title":"The Timing of the Excitatory-to-Inhibitory GABA Switch Is Regulated by the Oxytocin Receptor via KCC2","volume":"15","author":"Leonzino","year":"2016","journal-title":"Cell Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.neubiorev.2018.05.001","article-title":"Chloride transporters and GABA polarity in developmental, neurological and psychiatric conditions","volume":"90","author":"Schulte","year":"2018","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"re3","DOI":"10.1126\/scisignal.2005365","article-title":"The WNK-SPAK\/OSR1 pathway: Master regulator of cation-chloride cotransporters","volume":"7","author":"Alessi","year":"2014","journal-title":"Sci. Signal."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"14115","DOI":"10.1074\/jbc.M110.112672","article-title":"Multiple Pathways for Protein Phosphatase 1 (PP1) Regulation of Na-K-2Cl Cotransporter (NKCC1) Function: The N-terminal tail of the Na-K-2Cl cotransporter serves as a regulatory scaffold for Ste20-related proline\/alanine-rich kinase (SPAK) and PP1","volume":"285","author":"Gagnon","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2961","DOI":"10.1172\/JCI67510","article-title":"DISC1 and SLC12A2 interaction affects human hippocampal function and connectivity","volume":"123","author":"Callicott","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1093\/cercor\/bhq124","article-title":"Blocking early GABA depolarization with bumetanide results in permanent alterations in cortical circuits and sensorimotor gating deficits","volume":"21","author":"Wang","year":"2011","journal-title":"Cereb. Cortex"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Tang, B.L. (2020). The Expanding Therapeutic Potential of Neuronal KCC2. Cells, 9.","DOI":"10.3390\/cells9010240"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"174","DOI":"10.9758\/cpn.2020.18.2.174","article-title":"The Role of the SLC Transporters Protein in the Neurodegenerative Disorders","volume":"18","author":"Ayka","year":"2020","journal-title":"Clin. Psychopharmacol. Neurosci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/BF00308809","article-title":"Neuropathological staging of Alzheimer-related changes","volume":"82","author":"Braak","year":"1991","journal-title":"Acta Neuropathol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.tins.2007.05.001","article-title":"Human gamma-frequency oscillations associated with attention and memory","volume":"30","author":"Jensen","year":"2007","journal-title":"Trends Neurosci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1001\/archneurol.2009.15","article-title":"Epilepsy and Cognitive Impairments in Alzheimer Disease","volume":"66","author":"Palop","year":"2009","journal-title":"Arch. Neurol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1038\/nature07991","article-title":"Parvalbumin neurons and gamma rhythms enhance cortical circuit performance","volume":"459","author":"Sohal","year":"2009","journal-title":"Nature"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"8740","DOI":"10.1073\/pnas.1206171109","article-title":"Critical role of soluble amyloid-\u03b2 for early hippocampal hyperactivity in a mouse model of Alzheimer\u2019s disease","volume":"109","author":"Busche","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1016\/j.bbrc.2005.10.169","article-title":"\u03b2-amyloid increases dendritic Ca2+ influx by inhibiting the A-type K+ current in hippocampal CA1 pyramidal neurons","volume":"338","author":"Chen","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1016\/S0896-6273(03)00124-7","article-title":"APP Processing and Synaptic Function","volume":"37","author":"Kamenetz","year":"2003","journal-title":"Neuron"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1038\/nn.2583","article-title":"Amyloid-\u03b2-induced neuronal dysfunction in Alzheimer\u2019s disease: From synapses toward neural networks","volume":"13","author":"Mucke","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1111\/jnc.14325","article-title":"GABA A receptor subunit expression changes in the human Alzheimer\u2019s disease hippocampus, subiculum, entorhinal cortex and superior temporal gyrus","volume":"145","author":"Kwakowsky","year":"2018","journal-title":"J. Neurochem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1016\/j.neurobiolaging.2005.09.022","article-title":"Early neuropathology of somatostatin\/NPY GABAergic cells in the hippocampus of a PS1 x APP transgenic model of Alzheimer\u2019s disease","volume":"27","author":"Ramos","year":"2006","journal-title":"Neurobiol. Aging"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"13707","DOI":"10.1523\/JNEUROSCI.4040-10.2010","article-title":"Apolipoprotein E4 causes age- and Tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice","volume":"30","author":"Xu","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.4103\/1673-5374.235240","article-title":"Gamma-aminobutyric acid A receptors in Alzheimer\u2019s disease: Highly localized remodeling of a complex and diverse signaling pathway","volume":"13","author":"Kwakowsky","year":"2018","journal-title":"Neural Regen. Res."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Lam, P., Vinnakota, C., Guzm\u00e1n, B.C.-F., Newland, J., Peppercorn, K., Tate, W.P., Waldvogel, H.J., Faull, R.L.M., and Kwakowsky, A. (2022). Beta-Amyloid (A\u03b2 1-42 ) Increases the Expression of NKCC1 in the Mouse Hippocampus. Molecules, 27.","DOI":"10.3390\/molecules27082440"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"3072","DOI":"10.1016\/j.ymthe.2021.05.023","article-title":"Restoring neuronal chloride homeostasis with anti-NKCC1 gene therapy rescues cognitive deficits in a mouse model of Down syndrome","volume":"29","author":"Parrini","year":"2021","journal-title":"Mol. Ther."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.eplepsyres.2008.02.005","article-title":"NKCC1 and KCC2 prevent hyperexcitability in the mouse hippocampus","volume":"79","author":"Zhu","year":"2008","journal-title":"Epilepsy Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1111\/j.0953-816X.2003.03152.x","article-title":"Developmental changes in GABAergic actions and seizure susceptibility in the rat hippocampus","volume":"19","author":"Khazipov","year":"2004","journal-title":"Eur. J. Neurosci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"8465","DOI":"10.1073\/pnas.0602979103","article-title":"Anomalous Levels of Cl\u2212 Transporters in the Hippocampal Subiculum from Temporal Lobe Epilepsy Patients Make GABA Excitatory","volume":"103","author":"Palma","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.eplepsyres.2007.01.004","article-title":"Increased NKCC1 expression in refractory human epilepsy","volume":"74","author":"Sen","year":"2007","journal-title":"Epilepsy Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1038\/nm1301","article-title":"NKCC1 transporter facilitates seizures in the developing brain","volume":"11","author":"Dzhala","year":"2005","journal-title":"Nat. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1016\/S0306-4522(01)00149-X","article-title":"The differential expression patterns of messenger RNAs encoding K-Cl cotransporters (KCC1,2) and Na-K-2Cl cotransporter (NKCC1) in the rat nervous system","volume":"104","author":"Kanaka","year":"2001","journal-title":"Neuroscience"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1152\/ajpcell.1995.268.3.C747","article-title":"Cerebral microvascular endothelial cell Na-K-Cl cotransport: Regulation by astrocyte-conditioned medium","volume":"268","author":"Martinez","year":"1995","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1152\/ajpcell.1997.272.1.C173","article-title":"Expression of the Na(+)-K(+)-2Cl- cotransporter BSC2 in the nervous system","volume":"272","author":"Plotkin","year":"1997","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.neuropharm.2007.06.015","article-title":"Model-specific effects of bumetanide on epileptiform activity in the in-vitro intact hippocampus of the newborn mouse","volume":"53","author":"Kilb","year":"2007","journal-title":"Neuropharmacology"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"4695","DOI":"10.1523\/JNEUROSCI.19-12-04695.1999","article-title":"A Furosemide-Sensitive K+-Cl- Cotransporter Counteracts Intracellular Cl- Accumulation and Depletion in Cultured Rat Midbrain Neurons","volume":"19","author":"Jarolimek","year":"1999","journal-title":"J. Neurosci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1046\/j.0953-816x.2001.01854.x","article-title":"Postnatal maturation of Na+, K+, 2Cl- cotransporter expression and inhibitory synaptogenesis in the rat hippocampus: An immunocytochemical analysis","volume":"15","author":"Marty","year":"2002","journal-title":"Eur. J. Neurosci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.neuropharm.2012.05.045","article-title":"Cation-chloride cotransporters NKCC1 and KCC2 as potential targets for novel antiepileptic and antiepileptogenic treatments","volume":"69","author":"Puskarjov","year":"2013","journal-title":"Neuropharmacology"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"276","DOI":"10.55782\/ane-2014-1993","article-title":"BDNF modifies hippocampal KCC2 and NKCC1 expression in a temporal lobe epilepsy model","volume":"74","author":"Eftekhari","year":"2014","journal-title":"Acta Neurobiol. Exp."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"954167","DOI":"10.3389\/fnmol.2022.954167","article-title":"Imbalance between the function of Na(+)-K(+)-2Cl and K(+)-Cl impairs Cl(-) homeostasis in human focal cortical dysplasia","volume":"15","author":"Liu","year":"2022","journal-title":"Front. Mol. Neurosci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"F148","DOI":"10.1136\/adc.2004.068551","article-title":"Treatment of neonatal seizures","volume":"92","author":"Rennie","year":"2007","journal-title":"Arch. Dis. Child. Fetal Neonatal Ed."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.3389\/fneur.2019.01407","article-title":"Role of NKCC1 and KCC2 in Epilepsy: From Expression to Function","volume":"10","author":"Liu","year":"2020","journal-title":"Front. Neurol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1212\/CPJ.0b013e31823d07d1","article-title":"Treating patients with medically resistant epilepsy","volume":"1","author":"Krauss","year":"2011","journal-title":"Neurol. Clin. Pract."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.tips.2021.04.007","article-title":"Opportunities and challenges for microRNA-targeting therapeutics for epilepsy","volume":"42","author":"Morris","year":"2021","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1111\/epi.13965","article-title":"Commonalities in epileptogenic processes from different acute brain insults: Do they translate?","volume":"59","author":"Klein","year":"2018","journal-title":"Epilepsia"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1111\/j.1460-9568.2010.07122.x","article-title":"Expression pattern of miR-146a, an inflammation-associated microRNA, in experimental and human temporal lobe epilepsy","volume":"31","author":"Aronica","year":"2010","journal-title":"Eur. J. Neurosci."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1093\/bioinformatics\/btw008","article-title":"EpimiRBase: A comprehensive database of microRNA-epilepsy associations","volume":"32","author":"Mooney","year":"2016","journal-title":"Bioinformatics"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1002\/dvdy.24582","article-title":"MicroRNA-induced silencing in epilepsy: Opportunities and challenges for clinical application","volume":"247","author":"Tiwari","year":"2018","journal-title":"Dev. Dyn."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/nrg3965","article-title":"Towards a molecular understanding of microRNA-mediated gene silencing","volume":"16","author":"Jonas","year":"2015","journal-title":"Nat. Rev. Genet."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1038\/npp.2014.95","article-title":"Neurodevelopment, GABA system dysfunction, and schizophrenia","volume":"40","author":"Schmidt","year":"2015","journal-title":"Neuropsychopharmacology"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"15067","DOI":"10.1038\/nrdp.2015.67","article-title":"Schizophrenia","volume":"1","author":"Kahn","year":"2015","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1111\/nyas.12547","article-title":"The glutamate hypothesis of schizophrenia: Evidence from human brain tissue studies","volume":"1338","author":"Hu","year":"2015","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1038\/nrn1648","article-title":"Cortical inhibitory neurons and schizophrenia","volume":"6","author":"Lewis","year":"2005","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1073\/pnas.0910302107","article-title":"Neuregulin 1 Regulates Pyramidal Neuron Activity via ErbB4 in Parvalbumin-Positive Interneurons","volume":"107","author":"Wen","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1016\/j.cell.2011.12.037","article-title":"Interplay between DISC1 and GABA Signaling Regulates Neurogenesis in Mice and Risk for Schizophrenia","volume":"148","author":"Kim","year":"2012","journal-title":"Cell"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1016\/j.cell.2007.07.010","article-title":"Disrupted-In-Schizophrenia 1 Regulates Integration of Newly Generated Neurons in the Adult Brain","volume":"130","author":"Duan","year":"2007","journal-title":"Cell"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1080\/00048670701213245","article-title":"Gene expression profiling in Brodmann\u2019s area 46 from subjetcs with schizophrenia","volume":"41","author":"Dean","year":"2007","journal-title":"Aust. N. Z. J. Psychiatry"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1001\/archgenpsychiatry.2010.114","article-title":"Altered expression of regulators of the cortical chloride transporters NKCC1 and KCC2 in schizophrenia","volume":"68","author":"Arion","year":"2011","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"5216","DOI":"10.1523\/JNEUROSCI.4626-11.2012","article-title":"Transcript-specific associations of SLC12A5 (KCC2) in human prefrontal cortex with development, schizophrenia, and affective disorders","volume":"32","author":"Tao","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.jpsychires.2016.02.016","article-title":"Gain-of-function missense variant in SLC12A2, encoding the bumetanide-sensitive NKCC1 cotransporter, identified in human schizophrenia","volume":"77","author":"Merner","year":"2016","journal-title":"J. Psychiatr. Res."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"e202","DOI":"10.1038\/tp.2012.124","article-title":"A randomised controlled trial of bumetanide in the treatment of autism in children","volume":"2","author":"Lemonnier","year":"2012","journal-title":"Transl. Psychiatry"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1038\/s41467-019-13851-6","article-title":"Modulation of brain cation-Cl\u2212 cotransport via the SPAK kinase inhibitor ZT-1a","volume":"11","author":"Zhang","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"354","DOI":"10.3389\/fnhum.2017.00354","article-title":"Neurodevelopmental Hypothesis about the Etiology of Autism Spectrum Disorders","volume":"11","author":"Inui","year":"2017","journal-title":"Front. Hum. Neurosci."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"70","DOI":"10.3389\/fped.2014.00070","article-title":"GABAergic signaling as therapeutic target for autism spectrum disorders","volume":"2","author":"Cellot","year":"2014","journal-title":"Front. Pediatr."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"9929","DOI":"10.1523\/JNEUROSCI.1714-10.2010","article-title":"Defective GABAergic neurotransmission and pharmacological rescue of neuronal hyperexcitability in the amygdala in a mouse model of fragile X syndrome","volume":"30","author":"Paluszkiewicz","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1159\/000329420","article-title":"Fragile X Syndrome: The GABAergic System and Circuit Dysfunction","volume":"33","author":"Paluszkiewicz","year":"2011","journal-title":"Dev. Neurosci."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1126\/science.1247190","article-title":"Oxytocin-Mediated GABA Inhibition During Delivery Attenuates Autism Pathogenesis in Rodent Offspring","volume":"343","author":"Tyzio","year":"2014","journal-title":"Science"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"e68851","DOI":"10.1371\/journal.pone.0068851","article-title":"Abnormal expression of cerebrospinal fluid cation chloride cotransporters in patients with Rett syndrome","volume":"8","author":"Duarte","year":"2013","journal-title":"PLoS ONE"},{"key":"ref_107","first-page":"355","article-title":"Paradoxical reactions elicited by diazepam in children with classic autism","volume":"2","author":"Marrosu","year":"1987","journal-title":"Funct. Neurol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"e1124","DOI":"10.1038\/tp.2017.101","article-title":"Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders","volume":"7","author":"Lemonnier","year":"2017","journal-title":"Transl. Psychiatry"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1111\/j.1651-2227.2010.01933.x","article-title":"The diuretic bumetanide decreases autistic behaviour in five infants treated during 3 months with no side effects","volume":"99","author":"Lemonnier","year":"2010","journal-title":"Acta P\u00e6diatrica"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1177\/1362361313514141","article-title":"Improving emotional face perception in autism with diuretic bumetanide: A proof-of-concept behavioral and functional brain imaging pilot study","volume":"19","author":"Hadjikhani","year":"2015","journal-title":"Autism Int. J. Res. Pract."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"11811","DOI":"10.1074\/jbc.M213148200","article-title":"Identification of a Functionally Important Conformation-sensitive Region of the Secretory Na+-K+-2Cl\u2212 Cotransporter (NKCC1)*","volume":"278","author":"Dehaye","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1038\/s43587-021-00124-5","article-title":"A water pill against Alzheimer\u2019s disease","volume":"1","author":"Li","year":"2021","journal-title":"Nat. Aging"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1016\/j.tips.2021.09.005","article-title":"Pharmacological tools to target NKCC1 in brain disorders","volume":"42","author":"Savardi","year":"2021","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1038\/s43587-021-00122-7","article-title":"Experimental and real-world evidence supporting the computational repurposing of bumetanide for APOE4-related Alzheimer\u2019s disease","volume":"1","author":"Taubes","year":"2021","journal-title":"Nat. Aging"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.neuropharm.2004.04.002","article-title":"Chloride transport inhibitors influence recovery from oxygen\u2013glucose deprivation-induced cellular injury in adult hippocampus","volume":"47","author":"Pond","year":"2004","journal-title":"Neuropharmacology"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/S0006-8993(02)03832-5","article-title":"Inhibition of Na +\u2013K +\u2013Cl \u2212 cotransporter during focal cerebral ischemia decreases edema and neuronal damage","volume":"961","author":"Yan","year":"2003","journal-title":"Brain Res."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1038\/nn.4357","article-title":"Diminished KCC2 confounds synapse specificity of LTP during senescence","volume":"19","author":"Ferando","year":"2016","journal-title":"Nat. Neurosci."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"174771","DOI":"10.1016\/j.ejphar.2022.174771","article-title":"Suppression of hippocampal GABAergic transmission impairs memory in rodent models of Alzheimer\u2019s disease","volume":"917","author":"Bie","year":"2022","journal-title":"Eur. J. Pharmacol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1038\/s41467-018-03802-y","article-title":"GABAergic inhibition in dual-transmission cholinergic and GABAergic striatal interneurons is abolished in Parkinson disease","volume":"9","author":"Lozovaya","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"2073","DOI":"10.1016\/j.chempr.2020.06.017","article-title":"Discovery of a Small Molecule Drug Candidate for Selective NKCC1 Inhibition in Brain Disorders","volume":"6","author":"Savardi","year":"2020","journal-title":"Chem"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"eabg2648","DOI":"10.1126\/scisignal.abg2648","article-title":"Targeting ischemia-induced KCC2 hypofunction rescues refractory neonatal seizures and mitigates epileptogenesis in a mouse model","volume":"14","author":"Sullivan","year":"2021","journal-title":"Sci. Signal."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1016\/j.cell.2018.08.050","article-title":"Reactivation of Dormant Relay Pathways in Injured Spinal Cord by KCC2 Manipulations","volume":"174","author":"Chen","year":"2018","journal-title":"Cell"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1038\/nm.3356","article-title":"Chloride extrusion enhancers as novel therapeutics for neurological diseases","volume":"19","author":"Gagnon","year":"2013","journal-title":"Nat. Med."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1097\/WNF.0000000000000136","article-title":"Treating Schizophrenia With the Diuretic Bumetanide: A Case Report","volume":"39","author":"Lemonnier","year":"2016","journal-title":"Clin. Neuropharmacol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.schres.2016.12.002","article-title":"Effect of bumetanide, a selective NKCC1 inhibitor, on hallucinations of schizophrenic patients; a double-blind randomized clinical trial","volume":"184","author":"Rahmanzadeh","year":"2017","journal-title":"Schizophr. Res."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1016\/j.tips.2020.10.002","article-title":"A Novel Small Molecule Targets NKCC1 To Restore Synaptic Inhibition","volume":"41","author":"Raveendran","year":"2020","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/j.neuron.2009.03.003","article-title":"Cation-Chloride Cotransporters and Neuronal Function","volume":"61","author":"Blaesse","year":"2009","journal-title":"Neuron"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"310","DOI":"10.3389\/fnins.2019.00310","article-title":"Off-Label Use of Bumetanide for Brain Disorders: An Overview","volume":"13","author":"Kharod","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"26946","DOI":"10.1074\/jbc.274.38.26946","article-title":"Mice Lacking the Basolateral Na-K-2Cl Cotransporter Have Impaired Epithelial Chloride Secretion and Are Profoundly Deaf","volume":"274","author":"Flagella","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/S0003-9861(02)00047-4","article-title":"Expression and regulation of the Na +\/K +\/2Cl \u2212 cotransporter NKCC1 in rat liver and human HuH-7 hepatoma cells","volume":"401","author":"Schliess","year":"2002","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/S0166-2236(03)00068-7","article-title":"Cation\u2013chloride co-transporters in neuronal communication, development and trauma","volume":"26","author":"Payne","year":"2003","journal-title":"Trends Neurosci."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/s41398-020-0692-2","article-title":"Symptom improvement in children with autism spectrum disorder following bumetanide administration is associated with decreased GABA\/glutamate ratios","volume":"10","author":"Zhang","year":"2020","journal-title":"Transl. Psychiatry"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"C1516","DOI":"10.1152\/ajpcell.1997.273.5.C1516","article-title":"Functional characterization of the neuronal-specific K-Cl cotransporter: Implications for [K+](o) regulation","volume":"273","author":"Payne","year":"1997","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1074\/jbc.M509972200","article-title":"A C-terminal Domain in KCC2 Confers Constitutive K+-Cl- Cotransport","volume":"281","author":"Mercado","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.1523\/JNEUROSCI.20-04-01414.2000","article-title":"Localization and Developmental Expression Patterns of the Neuronal K-Cl Cotransporter (KCC2) in the Rat Retina","volume":"20","author":"Vu","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1016\/j.tins.2013.08.006","article-title":"Modulation of neuronal activity by phosphorylation of the K\u2013Cl cotransporter KCC2","volume":"36","author":"Kahle","year":"2013","journal-title":"Trends Neurosci."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"3199","DOI":"10.1111\/j.1460-9568.2003.03069.x","article-title":"Developmental up-regulation of KCC2 in the absence of GABAergic and glutamatergic transmission","volume":"18","author":"Ludwig","year":"2003","journal-title":"Eur. J. Neurosci."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1045520","DOI":"10.3389\/fphys.2022.1045520","article-title":"The role of KCC2 and NKCC1 in spinal cord injury: From physiology to pathology","volume":"13","author":"Talifu","year":"2022","journal-title":"Front. Physiol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1152\/physiol.00015.2009","article-title":"Molecular Mechanisms of Ischemic Cerebral Edema: Role of Electroneutral Ion Transport","volume":"24","author":"Kahle","year":"2009","journal-title":"Physiology"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"105441","DOI":"10.1016\/j.neuint.2022.105441","article-title":"Efficacy of novel SPAK inhibitor ZT-1a derivatives (1c, 1d, 1g & 1h) on improving post-stroke neurological outcome and brain lesion in mice","volume":"162","author":"Bhuiyan","year":"2022","journal-title":"Neurochem. Int."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1111\/jnc.14345","article-title":"The GABAergic system as a therapeutic target for Alzheimer\u2019s disease","volume":"146","author":"Vinnakota","year":"2018","journal-title":"J. Neurochem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/3\/1344\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:19:31Z","timestamp":1760120371000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/3\/1344"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,31]]},"references-count":141,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["molecules28031344"],"URL":"https:\/\/doi.org\/10.3390\/molecules28031344","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,31]]}}}