Skip to Main content Skip to Navigation
Journal articles

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

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.
Document type :
Journal articles
Complete list of metadatas

https://www.hal.inserm.fr/inserm-03000575
Contributor : Jean-Luc Gaiarsa <>
Submitted on : Thursday, November 12, 2020 - 8:17:00 AM
Last modification on : Friday, November 13, 2020 - 3:12:58 AM

Links full text

Identifiers

Collections

Citation

Lucie Pisella, Jean-Luc Gaiarsa, Diabé Diabira, Jinwei Zhang, Ilgam Khalilov, et al.. Impaired regulation of KCC2 phosphorylation leads to neuronal network dysfunction and neurodevelopmental pathology. Science Signaling, American Association for the Advancement of Science, 2019, 12 (603), pp.eaay0300. ⟨10.1126/scisignal.aay0300⟩. ⟨inserm-03000575⟩

Share

Metrics

Record views

14