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dc.contributor.authorPisella, LI
dc.contributor.authorGaiarsa, J-L
dc.contributor.authorDiabira, D
dc.contributor.authorZhang, J
dc.contributor.authorKhalilov, I
dc.contributor.authorDuan, J
dc.contributor.authorKahle, KT
dc.contributor.authorMedina, I
dc.date.accessioned2019-10-17T10:01:55Z
dc.date.issued2019-10-15
dc.description.abstractKCC2 is a vital neuronal K+/Cl− cotransporter that is implicated in the etiology of numerous neurological diseases. In normal cells, KCC2 undergoes developmental dephosphorylation at Thr906 and Thr1007. We engineered mice with heterozygous phosphomimetic mutations T906E and T1007E (KCC2E/+) to prevent the normal developmental dephosphorylation of these sites. Immature (postnatal day 15) but not juvenile (postnatal day 30) KCC2E/+ mice exhibited altered GABAergic inhibition, an increased glutamate/GABA synaptic ratio, and greater susceptibility to seizure. KCC2E/+ mice also had abnormal ultrasonic vocalizations at postnatal days 10 to 12 and impaired social behavior at postnatal day 60. Postnatal bumetanide treatment restored network activity by postnatal day 15 but failed to restore social behavior by postnatal day 60. Our data indicate that posttranslational KCC2 regulation controls the GABAergic developmental sequence in vivo, indicating that deregulation of KCC2 could be a risk factor for the emergence of neurological pathology.en_GB
dc.description.sponsorshipFrench Foundation of Epilepsy Research (FFRE)en_GB
dc.description.sponsorshipFrench Ministry of Education (MRT)en_GB
dc.description.sponsorshipMinistry of Education and Research of Russian Federationen_GB
dc.description.sponsorshipSimons Foundationen_GB
dc.description.sponsorshipMarch of Dimes Foundationen_GB
dc.description.sponsorshipNIHen_GB
dc.identifier.citationVol. 12 (603), article eaay0300en_GB
dc.identifier.doi10.1126/scisignal.aay0300
dc.identifier.grantnumber6.2313.2017/4.6en_GB
dc.identifier.grantnumber4K12NS080223-05en_GB
dc.identifier.urihttp://hdl.handle.net/10871/39247
dc.language.isoenen_GB
dc.publisherAmerican Association for the Advancement of Scienceen_GB
dc.rights© 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works http://www.sciencemag.org/about/science-licenses-journal-article-reuse This is an article distributed under the terms of the Science Journals Default License: https://www.sciencemag.org/about/science-licenses-journal-article-reuse?_ga=2.149494590.947419299.1571305760-231380269.1513172376en_GB
dc.titleImpaired regulation of KCC2 phosphorylation leads to neuronal network dysfunction and neurodevelopmental pathologyen_GB
dc.typeArticleen_GB
dc.date.available2019-10-17T10:01:55Z
dc.identifier.issn1945-0877
dc.descriptionThis is the author accepted manuscript. The final version is available from American Association for the Advancement of Science via the DOI in this recorden_GB
dc.descriptionData and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper or the Supplementary Materials.en_GB
dc.identifier.journalScience Signalingen_GB
dc.rights.urihttps://www.sciencemag.org/about/science-licenses-journal-article-reuse?_ga=2.149494590.947419299.1571305760-231380269.1513172376en_GB
dcterms.dateAccepted2019-08-30
rioxxterms.versionAMen_GB
rioxxterms.licenseref.startdate2019-10-15
rioxxterms.typeJournal Article/Reviewen_GB
refterms.dateFCD2019-10-17T09:58:18Z
refterms.versionFCDAM
refterms.dateFOA2019-10-17T10:02:01Z
refterms.panelAen_GB


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