title: Radixin regulates synaptic GABAA receptor density and is essential for reversal learning and short-term memory.
abstract: Neurotransmitter receptor density is a major variable in regulating synaptic strength. Receptors rapidly exchange between synapses and intracellular storage pools through endocytic recycling. In addition, lateral diffusion and confinement exchanges surface membrane receptors between synaptic and extrasynaptic sites. However, the signals that regulate this transition are currently unknown. GABAA receptors containing α5-subunits (GABAAR-α5) concentrate extrasynaptically through radixin (Rdx)-mediated anchorage at the actin cytoskeleton. Here we report a novel mechanism that regulates adjustable plasma membrane receptor pools in the control of synaptic receptor density. RhoA/ROCK signalling regulates an activity-dependent Rdx phosphorylation switch that uncouples GABAAR-α5 from its extrasynaptic anchor, thereby enriching synaptic receptor numbers. Thus, the unphosphorylated form of Rdx alters mIPSCs. Rdx gene knockout impairs reversal learning and short-term memory, and Rdx phosphorylation in wild-type mice exhibits experience-dependent changes when exposed to novel environments. Our data suggest an additional mode of synaptic plasticity, in which extrasynaptic receptor reservoirs supply synaptic GABAARs.
authors.affiliation: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology, ZMNH, Institut for Molecular Neurogenetics, Falkenried 94, 20251 Hamburg, Germany.
authors.forename: Torben J
authors.initials: TJ
authors.lastname: Hausrat
authors.affiliation: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology, ZMNH, Institut for Molecular Neurogenetics, Falkenried 94, 20251 Hamburg, Germany.
authors.forename: Mary
authors.initials: M
authors.lastname: Muhia
authors.affiliation: Biologie Cellulaire de la Synapse, Ecole Normale Supérieure, Inserm U1024, CNRS, UMR8197, PSL Research University, 46 rue d'Ulm, 75005 Paris, France.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Gerrow
authors.affiliation: University College London, Neuroscience, Physiology &Pharmacology, Gower Street, WC1E6BT London, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Thomas
authors.affiliation: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology, ZMNH, Institut for Molecular Neurogenetics, Falkenried 94, 20251 Hamburg, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Hirdes
authors.affiliation: Osaka University, Laboratory of Biological Science, Graduate School of Frontier Bioscience and Graduate School of Medicine, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Tsukita
authors.affiliation: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology, ZMNH, Institut for Molecular Neurogenetics, Falkenried 94, 20251 Hamburg, Germany.
authors.forename: Frank F
authors.initials: FF
authors.lastname: Heisler
authors.affiliation: University Medical Center Hamburg-Eppendorf, Medical Biometry and Epidemiology, Martinistraße 52, 20246 Hamburg, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Herich
authors.affiliation: Swiss Federal Institute of Technology Zurich, Behavioural Neurobiology, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Dubroqua
authors.affiliation: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology, ZMNH, Institut for Molecular Neurogenetics, Falkenried 94, 20251 Hamburg, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Breiden
authors.affiliation: Swiss Federal Institute of Technology Zurich, Behavioural Neurobiology, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland.
authors.forename: Joram
authors.initials: J
authors.lastname: Feldon
authors.affiliation: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology, ZMNH, Institut for Molecular Neurogenetics, Falkenried 94, 20251 Hamburg, Germany.
authors.forename: Jürgen R
authors.initials: JR
authors.lastname: Schwarz
authors.affiliation: Swiss Federal Institute of Technology Zurich, Behavioural Neurobiology, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland.
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Yee
authors.affiliation: University College London, Neuroscience, Physiology &Pharmacology, Gower Street, WC1E6BT London, UK.
authors.forename: Trevor G
authors.initials: TG
authors.lastname: Smart
authors.affiliation: Biologie Cellulaire de la Synapse, Ecole Normale Supérieure, Inserm U1024, CNRS, UMR8197, PSL Research University, 46 rue d'Ulm, 75005 Paris, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Triller
authors.affiliation: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology, ZMNH, Institut for Molecular Neurogenetics, Falkenried 94, 20251 Hamburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kneussel
mesh_terms: D000818:Animals; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D055724:Electrophysiological Phenomena; D005786:Gene Expression Regulation / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D007858:Learning / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000502:physiology*
chemical_list: D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D011963:Receptors, GABA-A; C071776:radixin