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Abstract
PSD-95 is a major scaffolding protein of the post-synaptic density (PSD) of a glutamatergic synapse. PSD-95, via interactions with stargazin, anchors AMPA receptors at the synapse and regulates AMPAR currents. The expression of PSD-95 is regulated during synaptic plasticity. It is, however, unknown whether this regulation is required for induction of functional plasticity of glutamatergic synapses. Here, we show that NMDA-induced long-term depression of synaptic transmission (NMDA-LTD) is accompanied by downregulation of PSD-95 protein levels. Using pharmacologic and molecular manipulations, we further demonstrate that the NMDA-induced downregulation of PSD-95 depends on the activation of CaMKII and CaMKII-driven phosphorylation of PSD-95 serine 73. Surprisingly, neither CaMKII activity nor CaMKII-dependent phosphorylation of PSD-95 serine 73 are required for the expression of NMDA-LTD. These results support the hypothesis that synaptic plasticity of AMPARs may occur without dynamic regulation of PSD-95 protein levels.
Highlights
post-synaptic density (PSD)-95 is the major scaffolding protein of a glutamatergic synapse[1] affecting its stability, activity-dependent modifications[2,3,4,5] and functional plasticity[6,7,8,9]
Using pharmacological manipulations and AAV transfection approach we found that NMDA-long-term depression (LTD)-induced downregulation of PSD-95 levels is regulated by CaMKII activity and CaMKII-driven phosphorylation of PSD-95:Ser[73]
organotypic hippocampal cultures (OHC) was chosen as a simplified model of the hippocampal formation that preserves most of the synaptic organization of the www.nature.com/scientificreports hippocampal area CA122. fEPSPs were recorded in the CA1 while stimulating the Schaffer collaterals in the CA3 (Fig. S1a)
Summary
PSD-95 is the major scaffolding protein of a glutamatergic synapse[1] affecting its stability, activity-dependent modifications[2,3,4,5] and functional plasticity[6,7,8,9]. PSD-95 is phosphorylated at serine 73 and transiently removed from the dendritic spine in a CaMKII-dependent manner[2]. Inhibition of this process by mutation of serine 73 to alanine does not affect the propensity to induce LTP2. Sturgill et al have shown that NMDA-LTD provokes rapid destabilization of PSD-95 in the spine head[4] It is yet unknown whether LTD-induced elimination of PSD-95 protein from the dendritic spine is necessary for the expression of LTD. Since it has been shown that CaMKII-dependent phosphorylation of PSD-95 on serine 73 (PSD-95:Ser73) regulates the binding of PSD-95 to NMDAR14 and translocation of PSD-95 from activated spines[2], we checked if CaMKII contributes to LTD-induced downregulation of PSD-95. Our data indicate dissociated function of CaMKII-dependent phosphorylation of PSD-95 in the regulation of molecular remodeling of synapses upon induction of NMDA-LTD and functional synaptic plasticity
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