{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T22:16:41Z","timestamp":1790806601077,"version":"4.1.0"},"reference-count":60,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2024,8,6]],"date-time":"2024-08-06T00:00:00Z","timestamp":1722902400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001665","name":"French national agency for research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["952096"],"award-info":[{"award-number":["952096"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,2,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Focal cortical dysplasia, hemimegalencephaly and cortical tubers are paediatric epileptogenic malformations of cortical development (MCDs) frequently pharmacoresistant and mostly treated surgically by the resection of epileptic cortex. Availability of cortical resection samples has allowed significant mechanistic discoveries directly from human material. Causal brain somatic or germline mutations in the AKT\/PI3K\/DEPDC5\/MTOR genes have been identified. GABAA-mediated paradoxical depolarization, related to altered chloride (Cl\u2212) homeostasis, has been shown to participate to ictogenesis in human paediatric MCDs. However, the link between genomic alterations and neuronal hyperexcitability is unclear. Here, we studied the post-translational interactions between the mTOR pathway and the regulation of cation\u2013chloride cotransporters (CCCs), KCC2 and NKCC1, that are largely responsible for controlling intracellular Cl\u2212 and, ultimately, GABAergic transmission.<\/jats:p>\n                  <jats:p>For this study, 35 children (25 MTORopathies and 10 pseudo-controls, diagnosed by histology plus genetic profiling) were operated for drug-resistant epilepsy. Postoperative cortical tissues were recorded on a multi-electrode array to map epileptic activities. CCC expression level and phosphorylation status of the WNK1\/SPAK-OSR1 pathway was measured during basal conditions and after pharmacological modulation. Direct interactions between mTOR and WNK1 pathway components were investigated by immunoprecipitation. Membranous incorporation of MCD samples in Xenopus laevis oocytes enabled measurement of the Cl\u2212 conductance and equilibrium potential for GABA.<\/jats:p>\n                  <jats:p>Of the 25 clinical cases, half harboured a somatic mutation in the mTOR pathway, and pS6 expression was increased in all MCD samples. Spontaneous interictal discharges were recorded in 65% of the slices. CCC expression was altered in MCDs, with a reduced KCC2\/NKCC1 ratio and decreased KCC2 membranous expression. CCC expression was regulated by the WNK1\/SPAK-OSR1 kinases through direct phosphorylation of Thr906 on KCC2, which was reversed by WNK1 and SPAK antagonists (N-ethylmaleimide and staurosporine). The mSIN1 subunit of MTORC2 was found to interact with SPAK-OSR1 and WNK1. Interactions between these key epileptogenic pathways could be reversed by the mTOR-specific antagonist rapamycin, leading to a dephosphorylation of CCCs and recovery of the KCC2\/NKCC1 ratio. The functional effect of such recovery was validated by the restoration of the depolarizing shift in the equilibrium potential for GABA by rapamycin, measured after incorporation of MCD membranes into X. laevis oocytes, in line with a re-establishment of normal Cl\u2212 reversal potential.<\/jats:p>\n                  <jats:p>Our study deciphers a protein interaction network through a phosphorylation cascade between MTOR and WNK1\/SPAK-OSR1 leading to deregulation of chloride cotransporters, increased neuronal Cl\u2212 levels and GABAA dysfunction in malformations of cortical development, linking genomic defects and functional effects and paving the way to target epilepsy therapy.<\/jats:p>","DOI":"10.1093\/brain\/awae262","type":"journal-article","created":{"date-parts":[[2024,8,4]],"date-time":"2024-08-04T09:30:40Z","timestamp":1722763840000},"page":"549-563","source":"Crossref","is-referenced-by-count":14,"title":["Chloride deregulation and GABA depolarization in MTOR-related malformations of cortical development"],"prefix":"10.1093","volume":"148","author":[{"given":"Naziha","family":"Bakouh","sequence":"first","affiliation":[{"name":"Translational Research in Neuroscience Lab, Institut Imagine, Universit\u00e9 Paris Cit\u00e9, INSERM U1163 , 75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reyes","family":"Casta\u00f1o-Mart\u00edn","sequence":"additional","affiliation":[{"name":"Translational Research in Neuroscience Lab, Institut Imagine, Universit\u00e9 Paris Cit\u00e9, INSERM U1163 , 75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Metais","sequence":"additional","affiliation":[{"name":"Institute of Psychiatry and Neuroscience of Paris (IPNP), Universit\u00e9 Paris Cit\u00e9, INSERM U1266 , 75014 Paris ,","place":["France"]},{"name":"Service de Neuropathologie, GHU-Paris Psychiatrie et Neurosciences, H\u00f4pital Sainte Anne , F-75014 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela Loredana","family":"Dan","sequence":"additional","affiliation":[{"name":"STAR-UBB Institute, Babe\u015f-Bolyai University , 400084 Cluj-Napoca ,","place":["Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estelle","family":"Balducci","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurosurgery H\u00f4pital Necker, Assistance Publique H\u00f4pitaux de Paris , 75015 Paris ,","place":["France"]},{"name":"Department of Pediatric Neurology, H\u00f4pital Necker, Assistance Publique H\u00f4pitaux de Paris , 75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cerina","family":"Chhuon","sequence":"additional","affiliation":[{"name":"INSERM US24, Proteomic platform, SFR Necker , 75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Lepicka","sequence":"additional","affiliation":[{"name":"INSERM US24, Proteomic platform, SFR Necker , 75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Barcia","sequence":"additional","affiliation":[{"name":"Translational Research in Neuroscience Lab, Institut Imagine, Universit\u00e9 Paris Cit\u00e9, INSERM U1163 , 75015 Paris ,","place":["France"]},{"name":"Department of Pediatric Neurosurgery H\u00f4pital Necker, Assistance Publique H\u00f4pitaux de Paris , 75015 Paris ,","place":["France"]},{"name":"Department of Pediatric Neurology, H\u00f4pital Necker, Assistance Publique H\u00f4pitaux de Paris , 75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Losito","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurosurgery H\u00f4pital Necker, Assistance Publique H\u00f4pitaux de Paris , 75015 Paris ,","place":["France"]},{"name":"Department of Pediatric Neurology, H\u00f4pital Necker, Assistance Publique H\u00f4pitaux de Paris , 75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phane","family":"Lourdel","sequence":"additional","affiliation":[{"name":"Cordeliers Research Center, INSERM, Sorbonne University, Paris Cit\u00e9 University , 75006 Paris ,","place":["France"]},{"name":"CNRS EMR 8228\u2014Laboratory of Renal Physiology and Tubulopathies , Universit\u00e9 de Paris Cit\u00e9, Centre de Recherche des Cordeliers, 75006 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabrielle","family":"Planelles","sequence":"additional","affiliation":[{"name":"Cordeliers Research Center, INSERM, Sorbonne University, Paris Cit\u00e9 University , 75006 Paris ,","place":["France"]},{"name":"CNRS EMR 8228\u2014Laboratory of Renal Physiology and Tubulopathies , Universit\u00e9 de Paris Cit\u00e9, Centre de Recherche des Cordeliers, 75006 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raul C","family":"Muresan","sequence":"additional","affiliation":[{"name":"STAR-UBB Institute, Babe\u015f-Bolyai University , 400084 Cluj-Napoca ,","place":["Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasile Vlad","family":"Moca","sequence":"additional","affiliation":[{"name":"STAR-UBB Institute, Babe\u015f-Bolyai University , 400084 Cluj-Napoca ,","place":["Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Kaminska","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurosurgery H\u00f4pital Necker, Assistance Publique H\u00f4pitaux de Paris , 75015 Paris ,","place":["France"]},{"name":"Department of Pediatric Neurology, H\u00f4pital Necker, Assistance Publique H\u00f4pitaux de Paris , 75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Bourgeois","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurosurgery H\u00f4pital Necker, Assistance Publique H\u00f4pitaux de Paris , 75015 Paris ,","place":["France"]},{"name":"Department of Pediatric Neurology, H\u00f4pital Necker, Assistance Publique H\u00f4pitaux de Paris , 75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Chemaly","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurosurgery H\u00f4pital Necker, Assistance Publique H\u00f4pitaux de Paris , 75015 Paris ,","place":["France"]},{"name":"Department of Pediatric Neurology, H\u00f4pital Necker, Assistance Publique H\u00f4pitaux de Paris , 75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmine","family":"Rguez","sequence":"additional","affiliation":[{"name":"Institute of Psychiatry and Neuroscience of Paris (IPNP), Universit\u00e9 Paris Cit\u00e9, INSERM U1266 , 75014 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3874-9749","authenticated-orcid":false,"given":"St\u00e9phane","family":"Auvin","sequence":"additional","affiliation":[{"name":"H\u00f4pital Robert Debr\u00e9, Assistance Publique H\u00f4pitaux de Paris , 75019 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilles","family":"Huberfeld","sequence":"additional","affiliation":[{"name":"Institute of Psychiatry and Neuroscience of Paris (IPNP), Universit\u00e9 Paris Cit\u00e9, INSERM U1266 , 75014 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascale","family":"Varlet","sequence":"additional","affiliation":[{"name":"Institute of Psychiatry and Neuroscience of Paris (IPNP), Universit\u00e9 Paris Cit\u00e9, INSERM U1266 , 75014 Paris ,","place":["France"]},{"name":"Service de Neuropathologie, GHU-Paris Psychiatrie et Neurosciences, H\u00f4pital Sainte Anne , F-75014 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vahid","family":"Asnafi","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurosurgery H\u00f4pital Necker, Assistance Publique H\u00f4pitaux de Paris , 75015 Paris ,","place":["France"]},{"name":"Department of Pediatric Neurology, H\u00f4pital Necker, Assistance Publique H\u00f4pitaux de Paris , 75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ida Chiara","family":"Guerrera","sequence":"additional","affiliation":[{"name":"INSERM US24, Proteomic platform, SFR Necker , 75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4118-251X","authenticated-orcid":false,"given":"Edor","family":"Kabashi","sequence":"additional","affiliation":[{"name":"Translational Research in Neuroscience Lab, Institut Imagine, Universit\u00e9 Paris Cit\u00e9, INSERM U1163 , 75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rima","family":"Nabbout","sequence":"additional","affiliation":[{"name":"Translational Research in Neuroscience Lab, Institut Imagine, Universit\u00e9 Paris Cit\u00e9, INSERM U1163 , 75015 Paris ,","place":["France"]},{"name":"Department of Pediatric Neurosurgery H\u00f4pital Necker, Assistance Publique H\u00f4pitaux de Paris , 75015 Paris ,","place":["France"]},{"name":"Department of Pediatric Neurology, 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