Moore, YE;
Conway, LC;
Wobst, HJ;
Brandon, NJ;
Deeb, TZ;
Moss, SJ;
(2019)
Developmental Regulation of KCC2 Phosphorylation Has Long-Term Impacts on Cognitive Function.
Frontiers in Molecular Neuroscience
, 12
, Article 173. 10.3389/fnmol.2019.00173.
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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.
| Type: | Article |
|---|---|
| Title: | Developmental Regulation of KCC2 Phosphorylation Has Long-Term Impacts on Cognitive Function |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3389/fnmol.2019.00173 |
| Publisher version: | https://doi.org/10.3389/fnmol.2019.00173 |
| Language: | English |
| Additional information: | Copyright © 2019 Moore, Conway, Wobst, Brandon, Deeb and Moss. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (http://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
| Keywords: | KCC2, depolarizing GABA, autism, cognition, social behavior, memory, phosphorylation |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10080430 |
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