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Sci Signal. 2019 Oct 15;12(603). pii: eaay0300. doi: 10.1126/scisignal.aay0300.

Impaired regulation of KCC2 phosphorylation leads to neuronal network dysfunction and neurodevelopmental pathology.

Author information

1
Aix-Marseille University, UMR 1249, INSERM (Institut National de la Santé et de la Recherche Médicale) Unité 1249, INMED (Institut de Neurobiologie de la Méditerranée), Marseille, France.
2
Institute of Biomedical and Clinical Sciences, College of Medicine and Health, University of Exeter Medical School, Hatherly Laboratories, Exeter EX4 4PS, UK.
3
Laboratory of Neurobiology, Kazan Federal University, Kazan 420008, Russia.
4
Department of Neurobiology, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
5
Departments of Neurosurgery, Pediatrics, and Cellular and Molecular Physiology and Centers for Mendelian Genomics, Yale School of Medicine, New Haven, CT 06510, USA.
6
Departments of Neurosurgery, Pediatrics, and Cellular and Molecular Physiology and Centers for Mendelian Genomics, Yale School of Medicine, New Haven, CT 06510, USA. igor.medyna@inserm.fr kristopher.kahle@yale.edu.
7
Aix-Marseille University, UMR 1249, INSERM (Institut National de la Santé et de la Recherche Médicale) Unité 1249, INMED (Institut de Neurobiologie de la Méditerranée), Marseille, France. igor.medyna@inserm.fr kristopher.kahle@yale.edu.

Abstract

KCC2 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.

PMID:
31615899
DOI:
10.1126/scisignal.aay0300

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