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Glutamate-Induced AMPA Receptor Desensitization Increases Their Mobility and Modulates Short-Term Plasticity Through Unbinding from Stargazin

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Glutamate-Induced AMPA Receptor Desensitization Increases Their Mobility and Modulates Short-Term Plasticity Through Unbinding from Stargazin Article Glutamate-Induced AMPA Receptor Desensitization Increases Their Mobility and Modulates Short-Term Plasticity through Unbinding from Stargazin Highlights Authors d Glutamate increases AMPA receptor diffusion in a Audrey Constals, Andrew C. Penn, ..., conformation-dependent manner Eric Hosy, Daniel Choquet d Desensitized AMPAR diffuse faster than closed-resting or Correspondence open ones [email protected] (E.H.), [email protected] (D.C.) d Preventing AMPAR-stargazin dissociation blocks glutamate- induced AMPAR diffusion In Brief d AMPAR-stargazin unbinding speeds recovery from synaptic Constals et al. use single-molecule short-term depression tracking to show that desensitized AMPA receptors diffuse faster than closed- resting or open ones through unbinding from stargazin. This allows AMPA receptor diffusion to accelerate recovery from short-term synaptic depression. Constals et al., 2015, Neuron 85, 787–803 February 18, 2015 ª2015 Elsevier Inc. http://dx.doi.org/10.1016/j.neuron.2015.01.012 Neuron Article Glutamate-Induced AMPA Receptor Desensitization Increases Their Mobility and Modulates Short-Term Plasticity through Unbinding from Stargazin Audrey Constals,1,2 Andrew C. Penn,1,2 Benjamin Compans,1,2 Estelle Toulme´ ,1,2 Amandine Phillipat,1,2 Se´ bastien Marais,3 Natacha Retailleau,1,2 Anne-Sophie Hafner,1,2 Franc¸ oise Coussen,1,2 Eric Hosy,1,2,4,* and Daniel Choquet1,2,3,4,* 1University of Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, F-33000 Bordeaux, France 2CNRS, Interdisciplinary Institute for Neuroscience, UMR 5297, F-33000 Bordeaux, France 3Bordeaux Imaging Center, UMS 3420 CNRS, US4 INSERM, University of Bordeaux, F-33000 Bordeaux, France 4Co-senior authors *Correspondence: [email protected] (E.H.), [email protected] (D.C.) http://dx.doi.org/10.1016/j.neuron.2015.01.012 SUMMARY through interactions between the various members of the AMPAR complex with a variety of intracellular and extracellular Short-term plasticity of AMPAR currents during high- partners (Jackson and Nicoll, 2011; Shepherd and Huganir, frequency stimulation depends not only on presyn- 2007). AMPAR are not all stable in the synapse and around aptic transmitter release and postsynaptic AMPAR 50% move constantly by Brownian diffusion within the plasma recovery from desensitization, but also on fast membrane, promoting continuous exchanges between synaptic AMPAR diffusion. How AMPAR diffusion within the and extrasynaptic sites. This proportion is highly regulated by synapse regulates synaptic transmission on the milli- neuronal activity and other stimuli (Choquet and Triller, 2013). The diffusion of AMPAR has long been considered to play a second scale remains mysterious. Using single- role only in controlling the accumulation of synaptic receptors molecule tracking, we found that, upon glutamate in time scales ranging from seconds to minutes (Choquet and binding, synaptic AMPAR diffuse faster. Using Triller, 2013; Shepherd and Huganir, 2007). In 2008, we pro- AMPAR stabilized in different conformational states posed a new physiological role for AMPAR diffusion in the con- by point mutations and pharmacology, we show trol of fast synaptic transmission over timescales of a few tens that desensitized receptors bind less stargazin and of milliseconds (Heine et al., 2008). We demonstrated, using are less stabilized at the synapse than receptors in paired-pulse stimulations in electrophysiological recordings opened or closed-resting states. AMPAR mobility- and crosslinking of surface AMPAR with antibodies, that the mediated regulation of short-term plasticity is rapid exchange of desensitized receptors by naive ones in the abrogated when the glutamate-dependent loss in synapse is essential to maintain the fidelity of high-frequency AMPAR-stargazin interaction is prevented. We pro- synaptic transmission. In addition, AMPAR stabilization by PSD-95-potentiated frequency-dependent synaptic depression pose that transition from the activated to the desen- (Opazo et al., 2010). Conversely, accelerating AMPAR move- sitized state leads to partial loss in AMPAR-stargazin ments by removing the extracellular matrix (Frischknecht et al., interaction that increases AMPAR mobility and 2009) accelerated recovery from paired-pulse depression. Alto- allows faster recovery from desensitization-medi- gether, we thus hypothesized that AMPAR diffusion allows syn- ated synaptic depression, without affecting the over- apses to sustain higher frequencies than the rate of AMPAR all nano-organization of AMPAR in synapses. return from desensitization would normally allow (Choquet, 2010). Upon glutamate release, the postsynaptic area in which AMPAR can be opened does not exceed 100–200 nm in diam- INTRODUCTION eter due to their low apparent affinity for glutamate (Lisman et al., 2007). Within this small area, rapidly diffusing receptors The alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic can be renewed up to 30% within 10 ms considering a homoge- acid (AMPA) subtype of glutamate receptors (AMPAR) mediates neous distribution of AMPAR at the synapse (Heine et al., 2008). most of fast excitatory synaptic transmission in the mammalian However, as more than 50% of receptors may be immobile in the central nervous system. AMPAR are formed of a core heterote- synapse (Ashby et al., 2006; Heine et al., 2008), this raises ques- trameric structure composed of a combination of four subunits, tions about the mechanisms through which AMPAR diffusion GluA1–GluA4 (Traynelis et al., 2010), surrounded by a variety of could allow a fast enough exchange of receptors to allow a auxiliary subunits (Schwenk et al., 2012). AMPAR are largely measurable impact on high frequency synaptic transmission. concentrated in the postsynaptic density (PSD), in front of pre- The nanoscale spatial distribution of AMPAR in the synapse is synaptic glutamate release sites, where they are stabilized highly heterogeneous (MacGillavry et al., 2013; Masugi-Tokita Neuron 85, 787–803, February 18, 2015 ª2015 Elsevier Inc. 787 A Homer-GFP 1 µm Control 100 µM Glutamate B Calcium imaging Glutamate Ctrl Blockers 0 F/F C Immobile Mobile Time (s) Ctrl ns Vehicle (H2O) ratio MSD (µm²) Occurrence (%) Occurrence Mobile/immobile Ctrl H2O D 2.5 0.06 Ctrl 2.0 * Glu (100µM) 1.5 0.04 ratio 1.0 0.02 0.5 MSD (µm²) Mobile/immobile Occurrence (%) 0.0 0.00 Ctrl Glu 0 500 1000 E (100 µM) Ctrl Glu (1 mM) ** ratio MSD (µm²) Mobile/immobile Occurrence (%) Ctrl Glu Time (ms) Log (D) (1 mM) FG **** *** *** *** Variation in MSD Variation in mobile fraction l M M Ctr µM µM m 1 µM 0 20 µ 00 1 10 3 (legend on next page) 788 Neuron 85, 787–803, February 18, 2015 ª2015 Elsevier Inc. and Shigemoto, 2007; Nair et al., 2013). About half of synaptic receptor mobility through conformation changes: desensitized AMPAR are packed and stabilized in clusters of about 80 nm receptors being more mobile and less confined than those in wide, each comprising about 20 receptors. The other half are the resting state due to specific unbinding of desensitized recep- mobile in between clusters (Nair et al., 2013). While this could tors from stargazin. This allows the desensitized fraction of re- help explain how AMPAR diffusion could contribute to short- ceptors to move away from the glutamate release site and term plasticity, the relative stability of AMPAR nanodomains still quickly be replaced by naive functional ones during synaptic poses the question of how a large proportion of trapped AMPAR transmission. Glutamate-mediated modulation of the mobility could be exchanged within a few milliseconds. state of desensitized AMPAR directly participates to the modu- Several molecular mechanisms are involved in controlling lation of frequency-dependent synaptic responses. AMPAR stabilization, among which those mediated by the trans- membrane AMPAR regulatory proteins (TARPs), and more par- RESULTS ticularly by stargazin, have been best characterized (Jackson and Nicoll, 2011). Stargazin is involved in stabilizing AMPAR in Glutamate Increases Mobility of Endogenous the PSD via its interaction with scaffolding proteins like PSD- GluA2-Containing AMPAR 95 (Bats et al., 2007; Opazo et al., 2010; Schnell et al., 2002) We first evaluated the impact of various doses of glutamate on which is increased in long-term potentiation (LTP) via a Cam- the surface mobility of whole cell (see Figures S1A and S1B KII-dependant phosphorylation of a stretch of serines in the star- available online) and synaptic (Figure 1) endogenous GluA2- gazin C-tail (Opazo et al., 2010; Tomita et al., 2005b). Stargazin containing AMPAR in conditions of minimal intracellular signaling also modulates receptor pharmacology and controls channel by using uPAINT single-molecule tracking of fluorescently gating: it increases AMPA receptor glutamate affinity, enhances labeled antibodies specific to the extracellular domain of GluA2 single-channel conductance, slows deactivation and desensiti- on dissociated hippocampal Banker cell cultures aged 13– zation, and reduces the extent of desensitization (Priel et al., 16 days in vitro (DIV) (Giannone et al., 2010). On average, about 2005; Tomita et al., 2005a; Turetsky et al., 2005). 1,500 fluorescent AMPAR-bound antibodies were tracked each The stability of stargazin (TARP)-AMPA receptor complex is for at least 0.5 s (median value of trajectory duration in seconds controversial. Both the native and recombinantly expressed with interquartile range [IQR],: 2.100 IQR 1.513–5.088), during complexes have been reported
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