Radixin regulates synaptic GABAA receptor density and is essential for reversal learning and short-term memory.
Torben J Hausrat, Mary Muhia, Kimberly Gerrow, Philip Thomas, Wiebke Hirdes, Sachiko Tsukita, Frank F Heisler, Lena Herich, Sylvain Dubroqua, Petra Breiden, Joram Feldon, Jürgen R Schwarz, Benjamin K Yee, Trevor G Smart, Antoine Triller, Matthias Kneussel
Author Information
Torben J Hausrat: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology, ZMNH, Institut for Molecular Neurogenetics, Falkenried 94, 20251 Hamburg, Germany.
Mary Muhia: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology, ZMNH, Institut for Molecular Neurogenetics, Falkenried 94, 20251 Hamburg, Germany.
Kimberly Gerrow: Biologie Cellulaire de la Synapse, Ecole Normale Supérieure, Inserm U1024, CNRS, UMR8197, PSL Research University, 46 rue d'Ulm, 75005 Paris, France.
Philip Thomas: University College London, Neuroscience, Physiology &Pharmacology, Gower Street, WC1E6BT London, UK.
Wiebke Hirdes: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology, ZMNH, Institut for Molecular Neurogenetics, Falkenried 94, 20251 Hamburg, Germany.
Sachiko Tsukita: Osaka University, Laboratory of Biological Science, Graduate School of Frontier Bioscience and Graduate School of Medicine, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan.
Frank F Heisler: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology, ZMNH, Institut for Molecular Neurogenetics, Falkenried 94, 20251 Hamburg, Germany.
Lena Herich: University Medical Center Hamburg-Eppendorf, Medical Biometry and Epidemiology, Martinistraße 52, 20246 Hamburg, Germany.
Sylvain Dubroqua: Swiss Federal Institute of Technology Zurich, Behavioural Neurobiology, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland.
Petra Breiden: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology, ZMNH, Institut for Molecular Neurogenetics, Falkenried 94, 20251 Hamburg, Germany.
Joram Feldon: Swiss Federal Institute of Technology Zurich, Behavioural Neurobiology, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland.
Jürgen R Schwarz: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology, ZMNH, Institut for Molecular Neurogenetics, Falkenried 94, 20251 Hamburg, Germany.
Benjamin K Yee: Swiss Federal Institute of Technology Zurich, Behavioural Neurobiology, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland.
Trevor G Smart: University College London, Neuroscience, Physiology &Pharmacology, Gower Street, WC1E6BT London, UK.
Antoine Triller: Biologie Cellulaire de la Synapse, Ecole Normale Supérieure, Inserm U1024, CNRS, UMR8197, PSL Research University, 46 rue d'Ulm, 75005 Paris, France.
Matthias Kneussel: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology, ZMNH, Institut for Molecular Neurogenetics, Falkenried 94, 20251 Hamburg, Germany.
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.
