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[ST8]: PSD‐MAGUK‐specific developmetal regulation of AMPA receptor synaptic expression
Author(s) -
Elias G.M.,
Funke L.,
Stein V.,
Grant S.G.,
Bredt D.S.,
Nicoll R.A.
Publication year - 2006
Publication title -
international journal of developmental neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.761
H-Index - 88
eISSN - 1873-474X
pISSN - 0736-5748
DOI - 10.1016/j.ijdevneu.2006.09.058
Subject(s) - library science , ampa receptor , medicine , receptor , computer science , glutamate receptor
upon Ca influx through activated N-methyl-D-aspartate subtype glutamate receptors (NMDARs). However, the mechanisms underlying the expression of LTP and LTD remain hotly debated, and likely involve both a presynaptic component via alteration of transmitter release and a postsynaptic one through the modification of (-amino-3hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptors (AMPARs). Traditionally, modifications of postsynaptic AMPARs has been thought to be achieved mainly by altering the channel gating properties or conductance of the receptors. Recent studies frommany laboratories including our own have provided substantial evidence suggesting that AMPARs are continuously cycling between the plasma membrane and intracellular compartments via vesicle fusion mediated plasma membrane insertion and clathrin dependent endocytosis and that facilitated AMPAR insertion and endocytosis at postsynaptic membranes contributes to the expression of LTP and LTD, respectively. Using a combination of recombinant receptor expression systems and hippocampal brain slice preparations, we were able to demonstrate that facilitated endocytosis of postsynaptic AMPAR during LTD is AMPARGluR2 subunit-specific. These studies have lead us to develop a GluR2-derived interference peptide that, when delivered into neurons in the brain, can specifically block the expression of LTD without affecting normal functioning of either NMDAR or AMPAR and hence, basal synaptic transmission in many regions of the brain. Using the membrane-permeate form of the GluR2 peptide as a specific inhibitor of LTD, we were able to probe the role of LTD in freely moving rats with unprecedented specificity and thereby provide evidence for the involvement of LTD in a number of learning and memory-related behaviours. Our work not only provides the first evidence for a definitive role of LTD in learning and memory, but also demonstrates the utility of peptides that disrupt the AMPAR trafficking, the final step in the expression of synaptic plasticity, as tools to examine the critical role of LTD and/or LTP in specific aspects of learning and memory in conscious animals.