The neuronal K-Cl cotransporter KCC2 influences postsynaptic AMPA receptor content and lateral diffusion in dendritic spines

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 37; pp. 15474 - 15479
• Main Authors: Gauvain, Grégory, Chamma, Ingrid, Chevy, Quentin, Cabezas, Carolina, Irinopoulou, Theano, Bodrug, Natalia, Carnaud, Michèle, Lévi, Sabine, Poncer, Jean Christophe
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 13.09.2011; National Acad Sciences
• Subjects: Actin; alpha -Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors; AMPA receptors; Animals; Biological Sciences; Cell adhesion molecules; Cell Adhesion Molecules, Neuronal - metabolism; Cell Membrane - metabolism; Cell membranes; Chloride; Chlorides; Cortex; Cytoskeleton; Dendritic spines; Dendritic Spines - metabolism; Diffusion; gamma -Aminobutyric acid; Gene expression; Glutamatergic transmission; Glutamic acid receptors (ionotropic); Hippocampus; Hippocampus - cytology; Homeostasis; Intracellular Space - metabolism; K Cl- Cotransporters; Lateral diffusion; Membrane proteins; Microfilaments; Morphogenesis; Neural cell adhesion molecules; Neurons; Neuroscience; Polarity; Potassium-chloride cotransporter; Protein Binding; Proteins; Rats; Rats, Sprague-Dawley; Receptors; Receptors, AMPA - metabolism; Signal transduction; Spine; Symporters - metabolism; Synapses; Synapses - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1107893108

The K-Cl cotransporter KCC2 plays an essential role in neuronal chloride homeostasis, and thereby influences the efficacy and polarity of GABA signaling. Although KCC2 is expressed throughout the somatodendritic membrane, it is remarkably enriched in dendritic spines, which host most glutamatergic synapses in cortical neurons. KCC2 has been shown to influence spine morphogenesis and functional maturation in developing neurons, but its function in mature dendritic spines remains unknown. Here, we report that suppressing KCC2 expression decreases the efficacy of excitatory synapses in mature hippocampal neurons. This effect correlates with a reduced postsynaptic aggregation of GluR1-containing AMPA receptors and is mimicked by a dominant negative mutant of KCC2 interaction with cytoskeleton but not by pharmacological suppression of KCC2 function. Single-particle tracking experiments reveal that suppressing KCC2 increases lateral diffusion of the mobile fraction of AMPA receptor subunit GluR1 in spines but not in adjacent dendritic shafts. Increased diffusion was also observed for transmembrane but not membrane-anchored recombinant neuronal cell adhesion molecules. We suggest that KCC2, likely through interactions with the actin cytoskeleton, hinders transmembrane protein diffusion, and thereby contributes to their confinement within dendritic spines.