Research ArticleNEURODEVELOPMENT

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

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Science Signaling  15 Oct 2019:
Vol. 12, Issue 603, eaay0300
DOI: 10.1126/scisignal.aay0300

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KCC2 in neuronal maturity

High intracellular concentrations of Cl ions in neurons interfere with synaptic signaling, particularly of the inhibitory neurotransmitter of the central nervous system (CNS), γ-aminobutyric acid (GABA), and are implicated in several neurological diseases, such as epilepsy and schizophrenia. By extruding Cl ions, the K+/Cl cotransporter KCC2 (encoded by SLC12A5) helps maintain Cl homeostasis. Watanabe et al. and Pisella et al. (see also the Focus by Zamponi) developed two knockin mouse models of constitutive KCC2 phosphorylation at two threonine sites and examined the consequential neurodevelopmental effects. Their findings show that dephosphorylation of these sites in KCC2 during CNS development in the mouse contributes to the GABA excitatory-to-inhibitory switch that promotes the neurocircuitry that underlies cognition, respiration, and other critical neurological physiology, thereby elucidating the causes of KCC2 (SLC12A5)–related pathologies.

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.

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