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 and Matthias Kneussel ()
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Torben J. Hausrat: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology
Mary Muhia: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology
Kimberly Gerrow: Biologie Cellulaire de la Synapse, Ecole Normale Supérieure
Philip Thomas: University College London, Neuroscience, Physiology & Pharmacology
Wiebke Hirdes: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology
Sachiko Tsukita: Osaka University, Laboratory of Biological Science, Graduate School of Frontier Bioscience and Graduate School of Medicine
Frank F. Heisler: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology
Lena Herich: University Medical Center Hamburg-Eppendorf, Medical Biometry and Epidemiology
Sylvain Dubroqua: Swiss Federal Institute of Technology Zurich, Behavioural Neurobiology
Petra Breiden: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology
Joram Feldon: Swiss Federal Institute of Technology Zurich, Behavioural Neurobiology
Jürgen R Schwarz: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology
Benjamin K. Yee: Swiss Federal Institute of Technology Zurich, Behavioural Neurobiology
Trevor G. Smart: University College London, Neuroscience, Physiology & Pharmacology
Antoine Triller: Biologie Cellulaire de la Synapse, Ecole Normale Supérieure
Matthias Kneussel: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology

Nature Communications, 2015, vol. 6, issue 1, 1-17

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7872

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