Molecular Dissociation of the Role of PSD-95 in Regulating Synaptic Strength and LTD

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2008 Jan 25

PMID 18215622

Citations 113

Authors

Weifeng Xu

Oliver M Schluter

Pascal Steiner

Brian L Czervionke

Bernardo Sabatini

Robert C Malenka

Affiliations

Soon will be listed here.

Abstract

The postsynaptic density protein PSD-95 influences synaptic AMPA receptor (AMPAR) content and may play a critical role in LTD. Here we demonstrate that the effects of PSD-95 on AMPAR-mediated synaptic responses and LTD can be dissociated. Our findings suggest that N-terminal-domain-mediated dimerization is important for PSD-95's effect on basal synaptic AMPAR function, whereas the C-terminal SH(3)-GK domains are also necessary for localizing PSD-95 to synapses. We identify PSD-95 point mutants (Q15A, E17R) that maintain PSD-95's influence on basal AMPAR synaptic responses yet block LTD. These point mutants increase the proteolysis of PSD-95 within its N-terminal domain, resulting in a C-terminal fragment that functions as a dominant negative likely by scavenging critical signaling proteins required for LTD. Thus, the C-terminal portion of PSD-95 serves a dual function. It is required to localize PSD-95 at synapses and as a scaffold for signaling proteins that are required for LTD.

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