Functional partnership between mGlu3 and mGlu5 metabotropic glutamate receptors in the central nervous system

Neuropharmacology. 2018 Jan:128:301-313. doi: 10.1016/j.neuropharm.2017.10.026. Epub 2017 Oct 25.

Abstract

mGlu5 receptors are involved in mechanisms of activity-dependent synaptic plasticity, and are targeted by drugs developed for the treatment of CNS disorders. We report that mGlu3 receptors, which are traditionally linked to the control of neurotransmitter release, support mGlu5 receptor signaling in neurons and largely contribute to the robust mGlu5 receptor-mediated polyphosphoinositide hydrolysis in the early postnatal life. In cortical pyramidal neurons, mGlu3 receptor activation potentiated mGlu5 receptor-mediated somatic Ca2+ mobilization, and mGlu3 receptor-mediated long-term depression in the prefrontal cortex required the endogenous activation of mGlu5 receptors. The interaction between mGlu3 and mGlu5 receptors was also relevant to mechanisms of neuronal toxicity, with mGlu3 receptors shaping the influence of mGlu5 receptors on excitotoxic neuronal death. These findings shed new light into the complex role played by mGlu receptors in physiology and pathology, and suggest reconsideration of some of the current dogmas in the mGlu receptor field.

Keywords: G-protein βγ subunits; Long-term depression; Metabotropic glutamate receptors; Neurodevelopment; Neuronal death; Polyphosphoinositide hydrolysis; Receptor-receptor cross-talk; Synaptic plasticity.

MeSH terms

  • Amino Acids / pharmacology
  • Animals
  • Animals, Newborn
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cells, Cultured
  • Central Nervous System / cytology
  • Central Nervous System / metabolism*
  • Embryo, Mammalian
  • Excitatory Amino Acid Agents / pharmacology
  • Female
  • Gene Expression Regulation, Developmental / drug effects
  • Gene Expression Regulation, Developmental / genetics
  • Humans
  • Hydrolysis / drug effects
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / physiology
  • Male
  • Methoxyhydroxyphenylglycol / analogs & derivatives
  • Methoxyhydroxyphenylglycol / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • N-Methylaspartate / pharmacology
  • Neurons / drug effects
  • Neurons / metabolism
  • Phosphatidylinositol Phosphates / metabolism
  • Rats
  • Receptor, Metabotropic Glutamate 5 / genetics
  • Receptor, Metabotropic Glutamate 5 / metabolism*
  • Receptors, Metabotropic Glutamate / genetics
  • Receptors, Metabotropic Glutamate / metabolism*

Substances

  • Amino Acids
  • Bridged Bicyclo Compounds, Heterocyclic
  • Excitatory Amino Acid Agents
  • LY 379268
  • Phosphatidylinositol Phosphates
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 3
  • Methoxyhydroxyphenylglycol
  • N-Methylaspartate
  • 3,4-dihydroxyphenylglycol