Developmentally regulated KCC2 phosphorylation is essential for dynamic GABA-mediated inhibition and survival

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Science Signaling  15 Oct 2019:
Vol. 12, Issue 603, eaaw9315
DOI: 10.1126/scisignal.aaw9315

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.

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