Coordination between Translation and Degradation Regulates Inducibility of mGluR-LTD

• mGluR-LTD can occur in the absence of an acute increase in dendritic protein levels
• mGluR-LTD leads to both synthesis and degradation of plasticity related proteins
• Proteasome inhibition rescues deficits in mGluR-LTD caused by blocking translation
• Sam68 is required for mGluR-induced ARC synthesis and LTD

SummaryDendritic protein homeostasis is crucial for most forms of long-term synaptic plasticity, and its dysregulation is linked to a wide range of brain disorders. Current models of metabotropic glutamate receptor mediated long-term depression (mGluR-LTD) suggest that rapid, local synthesis of key proteins is necessary for the induction and expression of LTD. Here, we find that mGluR-LTD can be induced in the absence of translation if the proteasome is concurrently inhibited. We report that enhanced proteasomal degradation during the expression of mGluR-LTD depletes dendritic proteins and inhibits subsequent inductions of LTD. Moreover, proteasome inhibition can rescue mGluR-LTD in mice null for the RNA binding protein Sam68, which we show here lack mGluR-dependent translation and LTD. Our study provides mechanistic insights for how changes in dendritic protein abundance regulate mGluR-LTD induction. We propose that Sam68-mediated translation helps to counterbalance degradation, ensuring that protein levels briefly remain above a permissive threshold during LTD induction.

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