Journal
NEURON
Volume 57, Issue 2, Pages 248-262Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2007.11.027
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Funding
- NIMH NIH HHS [R37 MH063394, R01 MH118298, R00 MH080310, K99 MH080310, K99 MH080310-01, MH063394, MH075220, F32 MH075220, R01 MH063394, MH080310] Funding Source: Medline
- NINDS NIH HHS [R01 NS052707, R01 NS052707-03] Funding Source: Medline
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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 SH3-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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