Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor number

Eric Schnell, Max Sizemore, Siavash Karimzadegan, Lu Chen, David S. Bredt, Roger A. Nicoll

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Abstract

Excitatory synapses in the brain exhibit a remarkable degree of functional plasticity, which largely reflects changes in the number of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). However, mechanisms involved in recruiting AMPARs to synapses are unknown. Here we use hippocampal slice cultures and biolistic gene transfections to study the targeting of AMPARs to synapses. We show that AMPARs are localized to synapses through direct binding of the first two PDZ domains of synaptic PSD-95 (postsynaptic density protein of 95 kDa) to the AMPAR-associated protein, stargazin. Increasing the level of synaptic PSD-95 recruits new AMPARs to synapses without changing the number of surface AMPARs. At the same time, we show that stargazin overexpression drastically increases the number of extrasynaptic AMPARs, but fails to alter synaptic currents if synaptic PSD-95 levels are kept constant. Finally, we make compensatory mutations to both PSD-95 and stargazin to demonstrate the central role of direct interactions between them in determining the number of synaptic AMPARs.

Original languageEnglish (US)
Pages (from-to)13902-13907
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number21
DOIs
StatePublished - Oct 15 2002

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