title: KCC2 Gates Activity-Driven AMPA Receptor Traffic through Cofilin Phosphorylation.
abstract: Expression of the neuronal K/Cl transporter KCC2 is tightly regulated throughout development and by both normal and pathological neuronal activity. Changes in KCC2 expression have often been associated with altered chloride homeostasis and GABA signaling. However, recent evidence supports a role of KCC2 in the development and function of glutamatergic synapses through mechanisms that remain poorly understood. Here we show that suppressing KCC2 expression in rat hippocampal neurons precludes long-term potentiation of glutamatergic synapses specifically by preventing activity-driven membrane delivery of AMPA receptors. This effect is independent of KCC2 transporter function and can be accounted for by increased Rac1/PAK- and LIMK-dependent cofilin phosphorylation and actin polymerization in dendritic spines. Our results demonstrate that KCC2 plays a critical role in the regulation of spine actin cytoskeleton and gates long-term plasticity at excitatory synapses in cortical neurons.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S 839, F-75005, Paris, France, Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, Unité Mixte de Recherche-S 839, F-75005, Paris, France, Institut du Fer a Moulin, F-75005, Paris, France, and.
authors.forename: Quentin
authors.identifier: http://orcid.org/0000-0002-4708-557X
authors.initials: Q
authors.lastname: Chevy
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S 839, F-75005, Paris, France, Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, Unité Mixte de Recherche-S 839, F-75005, Paris, France, Institut du Fer a Moulin, F-75005, Paris, France, and.
authors.forename: Martin
authors.initials: M
authors.lastname: Heubl
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S 839, F-75005, Paris, France, Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, Unité Mixte de Recherche-S 839, F-75005, Paris, France, Institut du Fer a Moulin, F-75005, Paris, France, and.
authors.forename: Marie
authors.initials: M
authors.lastname: Goutierre
authors.affiliation: Institut Cochin, Institut National de la Santé et de la Recherche Médicale, U 1016, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Université Paris Descartes, F-75014, Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Backer
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S 839, F-75005, Paris, France, Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, Unité Mixte de Recherche-S 839, F-75005, Paris, France, Institut du Fer a Moulin, F-75005, Paris, France, and.
authors.forename: Imane
authors.initials: I
authors.lastname: Moutkine
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S 839, F-75005, Paris, France, Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, Unité Mixte de Recherche-S 839, F-75005, Paris, France, Institut du Fer a Moulin, F-75005, Paris, France, and.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Eugène
authors.affiliation: Institut Cochin, Institut National de la Santé et de la Recherche Médicale, U 1016, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Université Paris Descartes, F-75014, Paris, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Bloch-Gallego
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S 839, F-75005, Paris, France, Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, Unité Mixte de Recherche-S 839, F-75005, Paris, France, Institut du Fer a Moulin, F-75005, Paris, France, and.
authors.forename: Sabine
authors.initials: S
authors.lastname: Lévi
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S 839, F-75005, Paris, France, Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, Unité Mixte de Recherche-S 839, F-75005, Paris, France, Institut du Fer a Moulin, F-75005, Paris, France, and jean-christophe.poncer@inserm.fr.
authors.forename: Jean Christophe
authors.identifier: http://orcid.org/0000-0001-5729-3009
authors.initials: JC
authors.lastname: Poncer
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism*; D000199:Actins / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000494:pharmacology; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005089:Exocytosis / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D013844:Thiazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013864:Thioglycolates / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000096922:K Cl- Cotransporters
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; D004318:Doxycycline; D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D018091:Receptors, AMPA; D027981:Symporters; D013844:Thiazoles; D013864:Thioglycolates; D000096922:K Cl- Cotransporters; C572191:N-(4-methylthiazol-2-yl)-2-(6-phenylpyridazin-3-ylthio)acetamide
keywords: AMPA receptor; KCC2; STED microscopy; actin; spine; synaptic plasticity