The Probability of Neurotransmitter Release Governs AMPA Receptor Trafficking via Activity-Dependent Regulation of mGluR1 Surface Expression

Cell Rep. 2018 Dec 26;25(13):3631-3646.e3. doi: 10.1016/j.celrep.2018.12.010.


A major mechanism contributing to synaptic plasticity involves alterations in the number of AMPA receptors (AMPARs) expressed at synapses. Hippocampal CA1 synapses, where this process has been most extensively studied, are highly heterogeneous with respect to their probability of neurotransmitter release, P(r). It is unknown whether there is any relationship between the extent of plasticity-related AMPAR trafficking and the initial P(r) of a synapse. To address this question, we induced metabotropic glutamate receptor (mGluR) dependent long-term depression (mGluR-LTD) and assessed AMPAR trafficking and P(r) at individual synapses, using SEP-GluA2 and FM4-64, respectively. We found that either pharmacological or synaptic activation of mGluR1 reduced synaptic SEP-GluA2 in a manner that depends upon P(r); this process involved an activity-dependent reduction in surface mGluR1 that selectively protects high-P(r) synapses from synaptic weakening. Consequently, the extent of postsynaptic plasticity can be pre-tuned by presynaptic activity.

Keywords: AMPA; DHPG; FM dye; LTD; Long-term depression; P(r); mGluR; metabotropic; probability of release; theta burst.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Membrane / metabolism*
  • Dendritic Spines / drug effects
  • Dendritic Spines / metabolism
  • Endocytosis / drug effects
  • Glutamates / metabolism
  • Long-Term Synaptic Depression / drug effects
  • Male
  • Methoxyhydroxyphenylglycol / analogs & derivatives
  • Methoxyhydroxyphenylglycol / pharmacology
  • Neurotransmitter Agents / metabolism*
  • Probability
  • Protein Transport / drug effects
  • Rats, Sprague-Dawley
  • Receptors, AMPA / metabolism*
  • Receptors, Metabotropic Glutamate / metabolism*
  • Synapses / drug effects
  • Synapses / metabolism
  • Theta Rhythm / drug effects


  • Glutamates
  • Neurotransmitter Agents
  • Receptors, AMPA
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor type 1
  • Methoxyhydroxyphenylglycol
  • 3,4-dihydroxyphenylglycol