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

Torben J Hausrat,Petra Breiden,Lena Herich,Frank F Heisler,Sachiko Tsukita,Sylvain Dubroqua,Philip Thomas,Trevor G Smart,Kimberly Gerrow,Wiebke Hirdes,Antoine Triller,Matthias Kneussel,Benjamin K Yee,Mary Muhia,Joram Feldon,Jürgen R Schwarz

doi:10.1038/ncomms7872

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.

Highlights

Neurotransmitter receptor density is a major variable in regulating synaptic strength
Receptors entered and left synaptic areas, with GABAA receptors (GABAARs)-a5 displaying significantly less confinement at inhibitory synapses compared with synaptically enriched receptors containing GABAAR-a2 (Fig. 1a,b) or GABAAR-a1 (Supplementary Fig. 1a,b)
Two populations of diffusing GABAAR-a5 were identified outside synapses: one with higher and one with lower diffusion coefficients compared with GABAAR-a2 (Fig. 1c,d, arrows) or GABAAR-a1 (Supplementary Fig. 1c,d, arrows)

Summary

Introduction

Neurotransmitter receptor density is a major variable in regulating synaptic strength. The majority of GABAAR-a5 receptors localize extrasynaptically and mediate tonic inhibition, a critical feature in the control of neuronal excitability, learning and memory[19,20]. It remains to be determined: (i) why extrasynaptic GABAAR-a5 surface membrane receptors accumulate extrasynaptically to synapses[7,21,22] and (ii) which parameters regulate the synaptic versus extrasynaptic localization of this receptor subtype. We report that Rdx-mediated extrasynaptic surface membrane clusters of GABAAR-a5 constitute potential reservoirs to rapidly supply GABAAR-a5 receptors to inhibitory synapses in an activity-dependent manner. Rdx depletion in mice impairs specific forms of learning and memory

Methods

Results

Conclusion