Developmental Regulation of KCC2 Phosphorylation Has Long-Term Impacts on Cognitive Function.

Yvonne E Moore,Heike J Wobst,Stephen J Moss,Tarek Z Deeb,Leslie C Conway,Nicholas J Brandon

doi:10.3389/fnmol.2019.00173

Abstract

GABAA receptor-mediated currents shift from excitatory to inhibitory during postnatal brain development in rodents. A postnatal increase in KCC2 protein expression is considered to be the sole mechanism controlling the developmental onset of hyperpolarizing synaptic transmission, but here we identify a key role for KCC2 phosphorylation in the developmental EGABA shift. Preventing phosphorylation of KCC2 in vivo at either residue serine 940 (S940), or at residues threonine 906 and threonine 1007 (T906/T1007), delayed or accelerated the postnatal onset of KCC2 function, respectively. Several models of neurodevelopmental disorders including Rett syndrome, Fragile × and Down’s syndrome exhibit delayed postnatal onset of hyperpolarizing GABAergic inhibition, but whether the timing of the onset of hyperpolarizing synaptic inhibition during development plays a role in establishing adulthood cognitive function is unknown; we have used the distinct KCC2-S940A and KCC2-T906A/T1007A knock-in mouse models to address this issue. Altering KCC2 function resulted in long-term abnormalities in social behavior and memory retention. Tight regulation of KCC2 phosphorylation is therefore required for the typical timing of the developmental onset of hyperpolarizing synaptic inhibition, and it plays a fundamental role in the regulation of adulthood cognitive function.

Highlights

Cl−-permeable Glycine and GABAA receptors are the exclusive mediators of fast synaptic inhibition in the central nervous system
Given that serine 940 (S940) phosphorylation scales with the developmental increase in total K+/Cl− cotransporter type 2 (KCC2) expression between 10 and 20 days in vitro (DIV), we hypothesized that S940 phosphorylation plays a role in the developmental regulation of KCC2 function
KCC2 is heavily phospho-regulated in the adult brain (Silayeva et al, 2015; Moore et al, 2017, 2018) and we have identified a critical role for phosphorylation in regulating KCC2 function during postnatal brain development

Summary

Introduction

Cl−-permeable Glycine and GABAA receptors are the exclusive mediators of fast synaptic inhibition in the central nervous system. During the early postnatal period, neurons have a high [Cl−]i, resulting in depolarizing responses to GABAA receptor activation, demonstrated through studies on the rodent brain (Ben-Ari et al, 1989, 2007; Owens et al, 1996). KCC2 Phosphorylation Regulates Cognition from depolarizing to hyperpolarizing (Rivera et al, 1999). This increase in Cl− extrusion is widely considered to be due to the functional upregulation of the neuron-specific K+/Cl− cotransporter type 2 (KCC2), which couples the outwardly directed K+ gradient to extrude Cl− from the cell against its concentration gradient (Li et al, 2002; Uvarov et al, 2006). KCC2 activity is essential for establishing the developmental onset of hyperpolarizing GABAA receptor currents

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Conclusion