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It is emerging that impaired K+\/Cl\u2212 cotransporter 2 (KCC2) activity leads to deficits in GABAergic inhibition and increased seizure vulnerability in patients. In neurons, the with-no-lysine (WNK) kinase-STE20\/SPS1-related proline\/alanine-rich (SPAK) kinase signalling pathway inhibits KCC2 activity via T1007 phosphorylation.<\/jats:p>\n                  <jats:p>Here, we exploit the selective WNK kinase inhibitor WNK463 to test the effects of pharmacological WNK inhibition on KCC2 function, GABAergic inhibition, and epileptiform activity. Immunoprecipitation and western blotting analysis revealed that WNK463 reduces KCC2-T1007 phosphorylation in vitro and in vivo. Using patch-clamp recordings in primary rat neurons, we further observed that WNK463 hyperpolarized the Cl\u2212 reversal potential, and enhanced KCC2-mediated Cl\u2212 extrusion. In the 4-aminopyridine slice model of acute seizures, WNK463 administration reduced the frequency and number of seizure-like events. In vivo, C57BL\/6 mice that received intrahippocampal WNK463 experienced delayed onset of kainic acid-induced status epilepticus, less epileptiform EEG activity, and did not develop pharmaco-resistance to diazepam. Our findings demonstrate that acute WNK463 treatment potentiates KCC2 activity in neurons and limits seizure burden in two well-established models of seizures and epilepsy.<\/jats:p>\n                  <jats:p>In summary, our work suggests that agents which act to increase KCC2 activity may be useful adjunct therapeutics to alleviate diazepam-resistant status epilepticus.<\/jats:p>","DOI":"10.1093\/brain\/awab343","type":"journal-article","created":{"date-parts":[[2021,9,10]],"date-time":"2021-09-10T15:09:34Z","timestamp":1631286574000},"page":"950-963","source":"Crossref","is-referenced-by-count":36,"title":["Inhibiting with-no-lysine kinases enhances K+\/Cl\u2212 cotransporter 2 activity and limits status epilepticus"],"prefix":"10.1093","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0079-9185","authenticated-orcid":false,"given":"Kathryn L","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krithika","family":"Abiraman","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Lucaj","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA"},{"name":"AstraZeneca-Tufts Laboratory of Basic and Translational Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas A","family":"Ollerhead","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J","family":"Brandon","sequence":"additional","affiliation":[{"name":"Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Boston, MA 02451, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tarek Z","family":"Deeb","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA"},{"name":"AstraZeneca-Tufts Laboratory of Basic and Translational Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie","family":"Maguire","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen J","family":"Moss","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA"},{"name":"AstraZeneca-Tufts Laboratory of Basic and Translational Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA"},{"name":"Department of Neuroscience, Physiology and Pharmacology, University College London, London WC16BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,9,16]]},"reference":[{"issue":"Pt 3","key":"2022042902241328700_awab343-B1","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1113\/jphysiol.2004.062471","article-title":"Cl- uptake promoting depolarizing GABA actions in immature rat neocortical neurones is mediated by NKCC1","volume":"557","author":"Yamada","year":"2004","journal-title":"J Physiol."},{"issue":"383","key":"2022042902241328700_awab343-B2","doi-asserted-by":"crossref","first-page":"ra65","DOI":"10.1126\/scisignal.aaa0354","article-title":"WNK1-regulated inhibitory phosphorylation of the KCC2 cotransporter maintains the depolarizing action of GABA in immature 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