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Nicoll, Roger
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| Research Statement | | | It is generally accepted that enduring changes in synaptic strength play a critical role in learning and memory. Long term potential (LTP), a phenomenon in which brief repetitive activation of excitatory synapses results in a long lasting enhancement in synaptic transmission, is the leading cellular model for learning and memory. After more than a decade of debate, there is now a consensus that the change in synaptic strength during LTP resides in the postsynaptic density (PSD). More specifically accumulating evidence indicates that LTP recruits AMPA receptors to the synapse. This research into synaptic plasticity has challenged the classical view of the synapse, in which receptors are firmly embedded in a rigid thicket of proteins in the PSD. Rather, the remarkably dynamic property of AMPA receptors rivals that usually associated with the presynaptic side of the synapse. In striking contrast, NMDA receptors, which intermingle with AMPA receptors, are relatively fixed components of the PSD. What accounts for the remarkable difference in the regulation of AMPA and NMDA receptors? I, in close collaboration with David Bredt, have identified two proteins that play an essential role in AMPA receptor trafficking and plasticity; PSD-95 and the tetraspanning membrane protein stargazin. The properties of PSD-95 make it an ideal candidate for determining the number of AMPA receptors that reside at a synapse. Stargazin, which binds both to PSD-95 and AMPA receptors, serves as the bridge. Furthermore, phosphorylation of stargazin plays a critical role in synaptic plasticity. Stargazin is a member of a family of closely related brain specific proteins. Our current research is focused on establishing whether our model can be extrapolated to all excitatory synapses in the CNS, to understand the topology of the stargazin/AMPA receptor interaction, and to determine how phosphorylation of stargazin controls synaptic strength. |
Publications | | Chen, L., Chetkovich, D.M., Petralia, R.S., Sweeney, N., Kawaski, Y., Wenthold, R.J., Bredt, D.S. and Nicoll, R.A.: Stargazin regulates the synaptic targeting of AMPA receptors by two
distinct mechanisms. Nature 408:936-943 (2000).
El-Husseini, A.E-D., Schnell, E., Dakoji, S., Sweeney, N., Zhou, Q., Prange, O., Gauthier-Campbell, Aguilera-Moreno, A., Nicoll, R.A. and Bredt, D.S.: Synaptic strength regulated by palmitate cycling on PSD-95. Cell 108:849-863 (2002).
Schnell, E., Sizemore, M., Karimzadegan, S., Chen, L., Bredt, D.S. and Nicoll, R.A.: Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor number. PNAS 99:13902-7 (2002).
Nicoll, R.A.: Expression mechanisms underlying long-term potentiation: a postsynaptic view. Phil. Trans. R. Soc. Lond. B Biol. Sci. 358:721-726 (2003).
Tomita, S., Fukata, M., Nicoll, R.A., and Bredt, D.S.: Dynamic Interaction of Stargazin-like TARPs with Cycling AMPA Receptors at Synapses. Science 303:1508-1511 (2004). |
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