Permissive role for mGlu1 metabotropic glutamate receptors in excitotoxic retinal degeneration. (5th November 2017)

• Record Type: Journal Article
• Authors: Liberatore, Francesca; Bucci, Domenico; Mascio, Giada; Madonna, Michele; Di Pietro, Paola; Beneventano, Martina; Puliti, Alda Maria; Battaglia, Giuseppe; Bruno, Valeria; Nicoletti, Ferdinando; Romano, Maria Rosaria
• Is Part Of: Neuroscience. Volume 363(2017)
• Page Start: 142
• Page End: 149
• Publication Date: 2017-11-05
• Subjects: mGlu metabotropic glutamate receptor -- MSG monosodium glutamate -- NAM negative allosteric modulator -- NMDA N-methyl-d-aspartate -- PI polyphosphoinositide -- PND post-natal day -- RGC retinal ganglion cell -- s.c. subcutaneous; retinal ganglion cells -- mGlu1 receptors -- monosodium glutamate -- JNJ16258695 -- crv4 mice; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2017.09.005
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: We used the monosodium glutamate model in mice to examine the role of mGlu1 receptors in retinal neurodegeneration. Systemic pharmacological blockade of mGlu1 receptors was protective against MSG-induced retinal ganglion cell loss. crv4 mice lacking mGlu1 receptors were resistant to MSG-induced retinal damage. mGlu1 receptor antagonists are promising candidate drugs for the treatment of retinal neurodegenerative disorders. Abstract: Neuroprotection is an unmet need in eye disorders characterized by retinal ganglion cell (RGC) death, such as prematurity-induced retinal degeneration, glaucoma, and age-related macular degeneration. In all these disorders excitotoxicity is a prominent component of neuronal damage, but clinical data discourage the development of NMDA receptor antagonists as neuroprotectants. Here, we show that activation of mGlu1 metabotropic glutamate receptors largely contributes to excitotoxic degeneration of RGCs. Mice at postnatal day 9 were challenged with a toxic dose of monosodium glutamate (MSG, 3 g/kg), which caused the death of >70% of Brn-3a + RGCs. Systemic administration of the mGlu1 receptor negative allosteric modulator (NAM), JNJ16259685 (2.5 mg/kg, s.c.), was largely protective against MSG-induced RGC death. This treatment did not cause changes in motor behavior in the pups. We also injected MSG to crv4 mice, which lack mGlu1 receptors because of a recessive mutation of the gene encoding the mGlu1 receptor. MSG did not cause retinal degeneration in crv4 mice, whereas it retained its toxic activity in their wild-type littermates. These findings demonstrate that mGlu1 receptors play a key role in excitotoxic degeneration of RGCs, and encourage the study of mGlu1 receptor NAMs in models of retinal neurodegeneration.