Ca2+/Calmodulin Binding to PSD-95 Downregulates Its Palmitoylation and AMPARs in Long-Term Depression.

Dhrubajyoti Chowdhury,Johannes W Hell

doi:10.3389/fnsyn.2019.00006

Dhrubajyoti Chowdhury, Johannes W Hell

Open Access

https://doi.org/10.3389/fnsyn.2019.00006

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Abstract

AMPA-type glutamate receptors (AMPARs) are clustered into functional nanodomains at postsynaptic sites through anchorage by the scaffolding protein, postsynaptic density protein-95 (PSD-95). The synaptic abundance of AMPARs is dynamically controlled in various forms of synaptic plasticity. Removal of AMPARs from the synapse in long-term depression (LTD) requires mobilization of PSD-95 away from the synapse. The molecular mechanisms underlying PSD-95 dispersal from the synapse during LTD are not completely understood. Here we show that, following Ca2+ influx, binding of Ca2+/calmodulin (CaM) to PSD-95 triggers loss of synaptic PSD-95 as well as surface AMPARs during chemically induced LTD in cultured rat neurons. Our data suggest that a reduction in PSD-95 palmitoylation mediates the effect of Ca2+/CaM on PSD-95 synaptic levels during LTD. These findings reveal a novel molecular mechanism for synaptic AMPAR regulation in LTD.

Highlights

Activity-dependent changes in the abundance of postsynaptic AMPA-type glutamate receptors (AMPARs) lie at the core of various long-lasting forms of synaptic plasticity (Henley and Wilkinson, 2016)
Using a molecular replacement strategy, we found that CaM binding to Glu 17 within the PSD-95 N-terminus is required for this reduction in PSD-95 palmitoylation and, as a consequence, dispersal of PSD95 from the synapse and downregulation of surface AMPARs in longterm depression (LTD)
Our findings provide a mechanistic basis for the removal of synaptic PSD-95 that is essential for AMPAR downregulation in LTD

Summary

Introduction

Activity-dependent changes in the abundance of postsynaptic AMPA-type glutamate receptors (AMPARs) lie at the core of various long-lasting forms of synaptic plasticity (Henley and Wilkinson, 2016). One such form of plasticity, long-term depression (LTD) involves removal of AMPARs from the synapse via molecular mechanisms that are incompletely understood (Collingridge et al, 2010). Through interaction of their auxiliary subunits, AMPARs are anchored to postsynaptic sites by scaffold proteins of which PSD-95 is the most abundant (Chen et al, 2005). Elucidating the molecular mechanisms of activity-driven changes in PSD-95 synaptic localization is fundamental to understand how synaptic plasticity at excitatory synapses is achieved

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