mGluR long‐term depression (mGluR‐LTD) is a form of synaptic plasticity induced at excitatory synapses by metabotropic glutamate receptors (mGluRs). mGluR‐LTD reduces synaptic strength and is relevant to learning and memory, autism, and sensitization to cocaine; however, the mechanism is not known. Here we show that activation of Group I mGluRs in medium spiny neurons induces trafficking of GluA2 from the endoplasmic reticulum (ER) to the synapse by enhancing GluA2 binding to essential COPII vesicle proteins, Sec23 and Sec13. GluA2 exit from the ER further depends on IP3 and Ryanodine receptor‐controlled Ca2+ release as well as active translation. Synaptic insertion of GluA2 is coupled to removal of high‐conducting Ca2+‐permeable AMPA receptors from synapses, resulting in synaptic depression. This work demonstrates a novel mechanism in which mGluR signals release AMPA receptors rapidly from the ER and couple ER release to GluA2 synaptic insertion and GluA1 removal.
DHPG induction of mGluR‐LTD induces a multi‐step program that drives GluA2 exit from the ER in COPII vesicles and inserts GluA2 at the synapse, while removing synaptic GluA1 homomers.
α‐Synuclein clusters within neuronal plasma membrane. In the first step, mGluR‐LTD stimulates protein synthesis, which increases the association of GluA2 with COPII vesicles.
In the second step, ER Ca2+ release driven by mGluR‐LTD selectively regulates GluA2 exit from the ER.
Induction of mGluR‐LTD by DHPG thereby increases surface GluA2 levels in a protein synthesis and ER Ca2+‐dependent manner.
mGluR‐LTD also drives the exchange of Ca2+‐permeable AMPARs with Ca2+‐impermeable AMPARs, which is ER calcium dependent.
- Received April 11, 2016.
- Revision received October 9, 2016.
- Accepted October 11, 2016.
- © 2016 The Authors