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

Luisa Di Menna, Max E. Joffe, Luisa Iacovelli, Rosamaria Orlando, Craig W. Lindsley, Jèrome Mairesse, Pierre Gressèns, Milena Cannella, Filippo Caraci, Agata Copani, Valeria Bruno, Giuseppe Battaglia, P. Jeffrey Conn, Ferdinando Nicoletti

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)301-313
Number of pages13
Publication statusE-pub ahead of print - Oct 25 2017


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

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience


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