Research ArticleNEURODEVELOPMENT

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

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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

Despite its importance for γ-aminobutyric acid (GABA) inhibition and involvement in neurodevelopmental disease, the regulatory mechanisms of the K+/Cl cotransporter KCC2 (encoded by SLC12A5) during maturation of the central nervous system (CNS) are not entirely understood. Here, we applied quantitative phosphoproteomics to systematically map sites of KCC2 phosphorylation during CNS development in the mouse. KCC2 phosphorylation at Thr906 and Thr1007, which inhibits KCC2 activity, underwent dephosphorylation in parallel with the GABA excitatory-inhibitory sequence in vivo. Knockin mice expressing the homozygous phosphomimetic KCC2 mutations T906E/T1007E (Kcc2E/E), which prevented the normal developmentally regulated dephosphorylation of these sites, exhibited early postnatal death from respiratory arrest and a marked absence of cervical spinal neuron respiratory discharges. Kcc2E/E mice also displayed disrupted lumbar spinal neuron locomotor rhythmogenesis and touch-evoked status epilepticus associated with markedly impaired KCC2-dependent Cl extrusion. These data identify a previously unknown phosphorylation-dependent KCC2 regulatory mechanism during CNS development that is essential for dynamic GABA-mediated inhibition and survival.

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