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

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 Ca 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.

Exposure to the predator odor TMT induces early and late differential gene expression related to stress and excitatory synaptic function throughout the brain in male rats

“…Interestingly, mGluR3mediated long-term depression (LTD) on excitatory prelimbic neurons was abolished following restraint stress 45 , which is consistent with our findings that TMT stress downregulates GRM3 expression in the prelimbic cortex. Therefore, the observed effects of predator odor stress on GRM3 gene expression may reflect stress-induced changes to synaptic plasticity that could in part underlie the observed changes in subsequent context re-exposure behavioral reactivity and gene expression changes related to the excitatory synapse 50 .…”

mGlu3 receptor regulates microglial cell reactivity in neonatal rats

“…mGlu3 receptors are different from mGlu2 receptors in that they boost mGlu5 receptor signaling, enhancing mGlu5 receptor-mediated phospho-inositide hydrolysis. Crosstalk between mGlu3 and mGlu5 receptors has been demonstrated in heterologous expression systems, brain slice preparations, cultured astrocytes (22), and cultured microglia (authors' unpublished observation).…”

“…The only published study concerning neonatal microglia reported a role for mGlu5 receptors in the control of neuro-inflammation following excitotoxic insult (7). Recent studies have shown that mGlu3 receptors boost mGlu5 receptor signaling in brain tissue and cultured astrocytes and that mGlu3 activation is required for a full mGlu5 receptor response to agonist activation (22)(23)(24). We therefore investigated whether mGlu3 receptors play a role in the modulation of brain inflammation, in particular in microglial cell reactivity.…”

D1-mGlu5 heteromers mediate noncanonical dopamine signaling in Parkinson’s disease

“…A total of 20 rats with unilateral 6-OHDA lesions were sacrificed by decapitation; striatal tissue was manually dissected out on ice and transferred on ice-cold Krebs-Henseleit buffer ( Slices were then incubated with LiCl (10 mM to block InsP degradation) and with the mGlu1 receptor antagonist JNJ16259685 (10 μM to block mGlu1 receptors). Thereafter, slices were stimulated with ligands of D1 and mGlu5 receptors at standard concentrations for this assay (74)(75). The following treatments were compared: (i) vehicle (basal levels), (ii) the D1 receptor agonist SKF38393 (200 μM), (iii) the group I mGlu receptor agonist DHPG (200 μM), (iv) the combina-…”