Destabilization of the Postsynaptic Density by PSD-95 Serine 73 Phosphorylation Inhibits Spine Growth and Synaptic Plasticity

Abstract

SUMMARY Long-term potentiation (LTP) is accompanied by dendritic spine growth and changes in the composition of the postsynaptic density (PSD). We find that activity-dependent growth of apical spines of CA1 pyramidal neurons is accompanied by destabilization of the PSD that results in transient loss and rapid replacement of PSD-95 and SHANK2. Signaling through PSD-95 is required for activity-dependent spine growth and trafficking of SHANK2. N-terminal PDZ and C-terminal guanylate kinase domains of PSD-95 are required for both processes, indicating that PSD-95 coordinates multiple signals to regulate morphological plasticity. Activity-dependent trafficking of PSD-95 is triggered by phosphorylation at serine 73, a conserved calcium/calmodulin-dependent protein kinase II (CaMKII) consensus phosphorylation site, which negatively regulates spine growth and potentiation of synaptic currents. We propose that PSD-95 and CaMKII act at multiple steps during plasticity induction to initially trigger and later terminate spine growth by trafficking growth-promoting PSD proteins out of the active spine.

Neurexin-Neuroligin Adhesions Capture Surface-Diffusing AMPA Receptors through PSD-95 Scaffolds

“…This concept of synaptic sharing is consistent with the facts that PSD-95 remodels within synapses and exchanges between synapses (Gray et al, 2006;Kuriu et al, 2006;Tsuriel et al, 2006;Blanpied et al, 2008;Steiner et al, 2008). The turnover rate of PSD-95 at synapses measured by FRAP is ϳ50 -60% in 30 min (Kuriu et al, 2006;Sharma et al, 2006;Tsuriel et al, 2006;Thoumine et al, 2008), indicating that novel Nrx/Nlg adhesions take up half this fraction of dynamic PSD-95.…”

Activity-Dependent Tau Protein Translocation to Excitatory Synapse Is Disrupted by Exposure to Amyloid-Beta Oligomers

“…The tau increase in the PSD-enriched fraction is concomitant with enrichment in PSD95 and GLUA1, both of which are necessary characteristics of synaptic potentiation (Ehlers, 2003;Steiner et al, 2008;Kessels and Malinow, 2009). Following the same behavior of well known plasticityrelated synaptic proteins such as GluA1, PSD-95, or actin suggests that tau may contribute to the functional modifications that sustain the enhanced synaptic strength associated with LTP.…”

IκB Kinase/Nuclear Factor κB-Dependent Insulin-Like Growth Factor 2 (Igf2) Expression Regulates Synapse Formation and Spine Maturation via Igf2 Receptor Signaling

“…6 D). As a control, we repressed CaMKII activity as a known kinase critically involved in synaptic maturation and plasticity (Vaillant et al, 2002;Steiner et al, 2008). In addition, we blocked MEK activity as an integral component of the RasRaf-MEK-ERK pathway (Harvey et al, 2008), GSK3␤ activity, as this is a proposed kinase acting downstream of Igf2R (D. Y. , and p38 activity, which was shown to preferentially act on presynaptic differentiation (Nakata et al, 2005).…”