Abstract
The regulated trafficking of neurotransmitter receptors at synapses is critical for synaptic function and plasticity. However, the molecular machinery that controls active transport of receptors into synapses is largely unknown. We found that, in rat hippocampus, the insertion of AMPA receptors (AMPARs) into spines during synaptic plasticity requires a specific motor protein, which we identified as myosin Va. We found that myosin Va associates with AMPARs through its cargo binding domain. This interaction was enhanced by active, GTP-bound Rab11, which is also transported by the motor protein. Myosin Va mediated the CaMKII-triggered translocation of GluR1 receptors from the dendritic shaft into spines, but it was not required for constitutive GluR2 trafficking. Accordingly, myosin Va was specifically required for long-term potentiation, but not for basal synaptic transmission. In summary, we identified the specific motor protein and organelle acceptor that catalyze the directional transport of AMPARs into spines during activity-dependent synaptic plasticity.
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Acknowledgements
We wish to dedicate this work to the memory of Alaa El-Husseini, a great friend and an outstanding scientist. We thank T. Robinson and J. Jedynak for the use of the Neurolucida software, V. Gelfand and R. Holz for the plasmid containing the mouse myosin Va globular tail, D. Wells and M. Mooseker for the human myosin VI, Y. Takagishi for the chicken full-length myosin Va, S. Lee for letting us test an unpublished siRNA against myosin Va (different from the one shown in this study) and R. Malinow for the PSD-95 construct. We also thank L. Weisman, M. Meisler and R. Holz for their comments on this work. This work was supported by grants from the US National Institute of Mental Health (MH070417 to J.A.E. and F31-MH070205 to T.C.B.), Fundação para a Ciência e a Tecnologia (SFRH/BPD/14620 to S.S.C.) and the European Community (LSHM-CT-2004-511995, SYNSCAFF to M.P.).
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S.S.C. is responsible for most of the experimental work. S.S.C. and J.A.E. designed the experiments and wrote the manuscript. S.B carried out the biochemical experiments of Figure 1 and the immunocytochemistry in Figure 2a,b. T.C.B. contributed some of the electrophysiology and imaging experiments. M.-F.L. developed and characterized the siRNA used in this study. D.S.B. carried out some of the initial cloning of this project. A.E.-H. and M.P. designed and supervised the experiments carried out by M.-F.L. and S.B., respectively.
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Correia, S., Bassani, S., Brown, T. et al. Motor protein–dependent transport of AMPA receptors into spines during long-term potentiation. Nat Neurosci 11, 457–466 (2008). https://doi.org/10.1038/nn2063
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DOI: https://doi.org/10.1038/nn2063
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