Selective activation of group III metabotropic glutamate receptor subtypes produces different patterns of γ‐aminobutyric acid immunoreactivity and glutamate release in the retina

Abstract

Glutamate, the major excitatory neurotransmitter in the retina, functions by activation of both ionotropic (iGluR) and metabotropic (mGluR) glutamate receptors. Group III mGluRs, except for mGluR6, are mostly found in the inner plexiform layer (IPL), and their retinal functions are not well known. Therefore, we decided to investigate the effect of mGluRIII on glutamate release and GABAergic amacrine cells in the chick retina. The nonselective mGluRIII agonist L-SOP promoted a decrease in the number of γ-aminobutyric acid (GABA)-positive cells and in the GABA immunoreactivity in all sublayers of the IPL. This effect was prevented by the antagonist MAP-4, by GAT-1 inhibitor, and by antagonists of iGluR. Under the conditions used, L-SOP did not alter endogenous glutamate release. VU0155041, an mGluR4-positive allosteric modulator, reduced GABA immunoreactivity in amacrine cells and in sublayers 2 and 4 of the IPL but evoked an increase in the glutamate released. VU0155041's effect was inhibited by the absence of calcium. AMN082, a selective mGluR7-positive allosteric modulator, also decreased GABA immunoreactivity in amacrine cells and sublayers 1, 2, and 3 and increased glutamate release, and this effect was also inhibited by calcium absence. DCPG, an mGluR8-selective agonist, did not significantly alter GABA immunoreactivity in amacrine cells or glutamate release. However, it did significantly increase GABA immunoreactivity in sublayers 4 and 5. The results suggest that mGluRIIIs are involved in the modulation of glutamate and GABA release in the retina, possibly participating in distinct visual pathways: mGluR4 might be involved with cholinergic circuitry, whereas mGluR7 and mGluR8 might participate, respectively, in the OFF and the ON pathways.

Activity of Metabotropic Glutamate Receptor 4 Suppresses Proliferation and Promotes Apoptosis With Inhibition of Gli-1 in Human Glioblastoma Cells

“…Furthermore, VU plays a specific role in activating mGluR4 without potentiating or abating other mGluR subtypes. Hence, VU may represent a breakthrough drug as well as a tool for the study of the role of mGluR4 in regulation of cell function in normal CNS and other cell types (Niswender et al, 2008 ; Betts et al, 2012 ; Guimarães-Souza and Calaza, 2012 ; Bogenpohl et al, 2013 ). In spite of its EC50 of 798 nM found in a human mGluR4 heterogeneous expression system, previous investigation reported that the effective concentrations of VU in cultured mouse cortical neurons were 10 and 30 μM, and VU did not exhibit obvious binding activity with off-target mGluR subtypes (Domin et al, 2016 ).…”

An Allosteric Regulator of R7-RGS Proteins Influences Light-Evoked Activity and Glutamatergic Waves in the Inner Retina

“…Indeed, activation of Gi/o-coupled A1 adenosine receptors can reduce RGC spiking by activating G-protein-coupled inwardly rectifying K + (GIRK) and small conductance Ca 2+ -activated K + (SK) channels [4]. Alternatively, activation of Gi/o-coupled group III mGluRs increases GABA release from amacrine cells and inhibitory drive experienced by RGCs [53].…”

Metabotropic glutamate receptor subtype 7 controls maternal care, maternal motivation and maternal aggression in mice

“…Mainly localized in the presynaptic zone of glutamate and GABA neurons,8–9 mGlu7 is thought to be an important regulator of glutamatergic and GABAergic neurotransmission with low affinity for glutamate and, thus, becomes activated by excessive glutamate release during very high synaptic activity 10–12. Importantly, due to its regulatory role of both glutamatergic and GABAergic neurotransmission in emotion and cognition circuitries in the brain, mGlu7 is thought to be a critical factor in the development of psychiatric and neurological disorders 10,13. So far, most studies using genetic and pharmacological approaches focused on the role of mGlu7 in fear, anxiety and other stress‐related mental and comorbid somatic disorders,14–16 whereas only few studies investigated the role of mGlu7 in complex social behaviors like intermale aggression.…”

“…[10][11][12] Importantly, due to its regulatory role of both glutamatergic and GABAergic neurotransmission in emotion and cognition circuitries in the brain, mGlu7 is thought to be a critical factor in the development of psychiatric and neurological disorders. 10,13 So far, most studies using genetic and pharmacological approaches focused on the role of mGlu7 in fear, anxiety and other stress-related mental and comorbid somatic disorders, [14][15][16] whereas only few studies investigated the role of mGlu7 in complex social behaviors like intermale aggression. Here, both mGlu7 activation via a selective agonist as well as genetic ablation reduced aggressive behavior toward a conspecific, 12,17 while intermale sexual behavior even increased in mGlu7 knockout (KO) males.…”