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  • br Introduction The development and plasticity

    2023-09-18


    Introduction The development and plasticity of synapses involve the timely recruitment of a plethora of proteins on both pre- and postsynaptic sides through ill-defined mechanisms. At excitatory synapses, two of the major proteins that are dynamically recruited postsynaptically are the Ca2+/calmodulin-dependent kinase II (CaMKII) and the AMPA-type glutamate receptor (AMPAR). Numerous studies have shown that CaMKII is involved in the activity and NMDA receptor (NMDAR)-dependent recruitment of AMPARs both during synaptic development and synaptic plasticity (Asrican et al., 2007, Hayashi et al., 2000, Lee et al., 2009, Lisman et al., 2002, Merrill et al., 2005, Pettit et al., 1994, Poncer et al., 2002, Rongo and Kaplan, 1999, Sanhueza et al., 2007, Zhang et al., 2008). However, it is unknown how CaMKII increases the number of AMPARs at synapses. Two principal recruitment mechanisms can be anticipated: CaMKII might promote the Efaproxiral Sodium of AMPAR-containing vesicles and/or the trapping at the postsynaptic density (PSD) of laterally diffusing AMPARs. While the evidence linking CaMKII activation and AMPAR recruitment at synapses has been interpreted via the exocytosis mechanism (Maletic-Savatic et al., 1998), the hypothesis that CaMKII can recruit AMPARs by diffusional trapping has not been examined, even though a number of findings indirectly support it (Lisman and Zhabotinsky, 2001). First, NMDAR activation causes the rapid translocation of CaMKII from dendritic compartments to activated synapses (Hudmon et al., 2005, Shen and Meyer, 1999, Strack et al., 1997). Second, following NMDAR activation, CaMKII can remain at postsynaptic sites for prolonged periods of time, through binding to several PSD proteins, including the NMDAR (Bayer et al., 2006, Lisman et al., 2002, Otmakhov et al., 2004). Third, CaMKII bound to the NMDAR remains active independent of Ca2+/CaM (Bayer et al., 2001), which should allow it to phosphorylate incoming membrane-bound proteins. Fourth, AMPARs are highly mobile at the neuronal surface, rapidly switching between extrasynaptic and synaptic sites (Bats et al., 2007, Borgdorff and Choquet, 2002, Heine et al., 2008, Tardin et al., 2003). Fifth, NMDAR stimulation, high-frequency stimulation, or increases in intracellular Ca2+ (Borgdorff and Choquet, 2002, Heine et al., 2008, Makino and Malinow, 2009, Petrini et al., 2009) all promote the rapid immobilization of AMPARs. Taken together, these findings suggest a scenario in which AMPARs are intrinsically mobile at the neuronal surface and can be “trapped” at activated synapses in a CaMKII-dependent manner. In this study, we asses directly whether CaMKII activation and postsynaptic translocation can recruit AMPARs at synapses by trapping the freely diffusing receptors in the plasma membrane. To this end, we either activated or inhibited CaMKII using a number of genetic, pharmacological, and physiological approaches while simultaneously tracking the mobility of surface AMPARs imaged via luminescent semiconductor quantum dots (QDs) precoupled to specific antibodies against AMPAR subunits (GluA1 or GluA2, corresponding to GluR1 and GluR2 [Collingridge et al., 2009]). Our results indicate that CaMKII activation stops the diffusion of surface AMPARs at synaptic sites. Furthermore, we show that this novel function of CaMKII is mediated by phosphorylation of stargazin and binding of its C terminus to PDZ domain scaffold proteins such as PSD95. Finally, we show that this CaMKII-dependent trapping of AMPARs to synaptic sites has a strong impact on paired-pulse depression, a form of short-term plasticity strongly dependent on the lateral mobility of AMPARs. Our experiments shine new light into the dynamic interaction between two key components of excitatory synapses and their fine tuning of synaptic transmission.
    Results
    Discussion Our study reveals a function of CaMKII as a regulator of AMPAR diffusional trapping at the synaptic surface and short-term synaptic plasticity. As shown in the model (Figure 7), we uncovered the molecular mechanisms underlying the Ca2+-dependent AMPAR trapping at synapses which involves the postsynaptic translocation of CaMKII and the direct phosphorylation of the AMPAR auxiliary subunit Stargazin.