Metabotropic Glutamate Receptors in Glial Cells: A New Potential Target for Neuroprotection?

Abstract

Neurodegenerative disorders are characterized by excitotoxicity and neuroinflammation that finally lead to slow neuronal degeneration and death. Although neurons are the principal target, glial cells are important players as they contribute by either exacerbating or dampening the events that lead to neuroinflammation and neuronal damage. A dysfunction of the glutamatergic system is a common event in the pathophysiology of these diseases. Metabotropic glutamate (mGlu) receptors belong to a large family of G protein-coupled receptors largely expressed in neurons as well as in glial cells. They often appear overexpressed in areas involved in neurodegeneration, where they can modulate glutamatergic transmission. Of note, mGlu receptor upregulation may involve microglia or, even more frequently, astrocytes, where their activation causes release of factors potentially able to influence neuronal death. The expression of mGlu receptors has been also reported on oligodendrocytes, a glial cell type specifically involved in the development of multiple sclerosis. Here we will provide a general overview on the possible involvement of mGlu receptors expressed on glial cells in the pathogenesis of different neurodegenerative disorders and the potential use of subtype-selective mGlu receptor ligands as candidate drugs for the treatment of neurodegenerative disorders. Negative allosteric modulators (NAM) of mGlu5 receptors might represent a relevant pharmacological tool to develop new neuroprotective strategies in these diseases. Recent evidence suggests that targeting astrocytes and microglia with positive allosteric modulators (PAM) of mGlu3 receptor or oligodendrocytes with mGlu4 PAMS might represent novel pharmacological approaches for the treatment of neurodegenerative disorders.

Reactive Astrocytes as Therapeutic Targets for Brain Degenerative Diseases: Roles Played by Metabotropic Glutamate Receptors

“…A number of studies have focused on astrocytic mGluRs as targets that can be manipulated to enhance repair after injury [5,31,45,49,50]. mGluRs, particularly mGluR3 and mGluR5, are the two most abundant mGluRs found on astrocytes [29,51].…”

“…mGluRs are G protein-coupled receptors consisting of seven transmembrane domains that are subdivided into Group I, II, and III based on their signaling transduction pathways, amino acid sequence homology, and selectivity of agonists and antagonists [1,2,5,59,60]. mGluR5, in addition to mGluR1, is classified as a Group I mGluR, while mGluR3 is part of the Group II mGluRs along with mGluR2.…”

“…We recognize that other glial cells react to mGluR stimulation as well as other activating influences. For a more comprehensive analysis of responses of these cells we refer the reader to excellent additional reviews of this subject [1][2][3][4][5].…”

mGlu3 receptor regulates microglial cell reactivity in neonatal rats

“…Targeting mGlu receptors represents a realistic therapeutic strategy due to the availability of allosteric modulators with long-lasting effects and a better safety profile than pharmacological agents that modulate ionotropic glutamate receptors. Indeed, recent evidence shows positive allosteric modulators of mGlu3 receptors in astrocytes or mGlu4 receptors in oligodendrocytes to be promising pharmacological approaches for the treatment of neurodegenerative disorders (21).…”

Effects of Cerebrospinal Fluid AMPA Receptor Levels on the Clinical Efficacy of Lamotrigine in Epilepsy Treatment

“…Glutamate receptors represent the majority of excitatory neurotransmission receptors in the central nervous system among mammals, and these receptors are divided into ionotropic and metabotropic [8] . Specifically, ionotropic glutamate receptors contain N-methyl-D-aspartate (NMDA), AMPA receptors and kainite (KA), which are the main mediators of brain function, such as synaptic transmission, long-term synaptic potentiation, synaptic plasticity and learning/memorization [9] .…”