mGlu1 tonically regulates levels of calcium-permeable AMPA receptors in cultured nucleus accumbens neurons through retinoic acid signaling and protein translation

Eur J Neurosci. 2019 Aug;50(3):2590-2601. doi: 10.1111/ejn.14151. Epub 2018 Oct 14.


In several brain regions, ongoing metabotropic glutamate receptor 1 (mGlu1) transmission has been shown to tonically suppress synaptic levels of Ca2+ -permeable AMPA receptors (CP-AMPARs) while pharmacological activation of mGlu1 removes CP-AMPARs from these synapses. Consistent with this, we previously showed in nucleus accumbens (NAc) medium spiny neurons (MSNs) that reduced mGlu1 tone enables and mGlu1 positive allosteric modulation reverses the elevation of CP-AMPAR levels in the NAc that underlies enhanced cocaine craving in the "incubation of craving" rat model of addiction. To better understand mGlu1/CP-AMPAR interactions, we used a NAc/prefrontal cortex co-culture system in which NAc MSNs express high CP-AMPAR levels, providing an in vitro model for NAc MSNs after the incubation of cocaine craving. The non-specific group I orthosteric agonist dihydroxyphenylglycine (10 min) decreased cell surface GluA1 but not GluA2, indicating CP-AMPAR internalization. This was prevented by mGlu1 (LY367385) or mGlu5 (MTEP) blockade. However, a selective role for mGlu1 emerged in studies of long-term antagonist treatment. Thus, LY367385 (24 hr) increased surface GluA1 without affecting GluA2, whereas MTEP (24 hr) had no effect. In hippocampal neurons, scaling up of CP-AMPARs can occur through a mechanism requiring retinoic acid (RA) signaling and new GluA1 synthesis. Consistent with this, the LY367385-induced increase in surface GluA1 was blocked by anisomycin (translation inhibitor) or 4-(diethylamino)-benzaldehyde (RA synthesis inhibitor). Thus, mGlu1 transmission tonically suppresses cell surface CP-AMPAR levels, and decreasing mGlu1 tone increases surface CP-AMPARs via RA signaling and protein translation. These results identify a novel mechanism for homeostatic plasticity in NAc MSNs.

Keywords: GluA1; group I metabotropic glutamate receptors; homeostatic plasticity; primary culture; receptor trafficking.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzoates / pharmacology
  • Calcium / metabolism*
  • Cells, Cultured
  • Excitatory Amino Acid Antagonists / pharmacology
  • Female
  • Glycine / analogs & derivatives
  • Glycine / pharmacology
  • Methoxyhydroxyphenylglycol / analogs & derivatives
  • Methoxyhydroxyphenylglycol / pharmacology
  • Mice
  • Mice, 129 Strain
  • Mice, Transgenic
  • Neurons / drug effects
  • Neurons / metabolism
  • Nucleus Accumbens / cytology
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism*
  • Pregnancy
  • Protein Biosynthesis / drug effects
  • Protein Biosynthesis / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / antagonists & inhibitors
  • Receptors, AMPA / metabolism*
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors
  • Receptors, Metabotropic Glutamate / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Tretinoin / metabolism*


  • Benzoates
  • Excitatory Amino Acid Antagonists
  • Receptors, AMPA
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor type 1
  • alpha-methyl-4-carboxyphenylglycine
  • Methoxyhydroxyphenylglycol
  • Tretinoin
  • Calcium
  • Glycine
  • 3,4-dihydroxyphenylglycol