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Radixin regulates synaptic GABAA receptor density and is essential for reversal learning and short-term memory

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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, 2015. "Radixin regulates synaptic GABAA receptor density and is essential for reversal learning and short-term memory," Nature Communications, Nature, vol. 6(1), pages 1-17, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7872
    DOI: 10.1038/ncomms7872
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