The Use of Knock-Out Mice Unravels Distinct Roles for mGlu2 and mGlu3 Metabotropic Glutamate Receptors in Mechanisms of Neurodegeneration/Neuroprotection

Abstract

Dual metabotropic glutamate 2/3 (mGlu2/3) receptor agonists have been examined with success in the clinic with positive proof of efficacy in several tests of anxiety and schizophrenia. Moreover, a large body of evidence has accumulated that these drugs have significant neuroprotective potential. An important discussion in the field deals with dissecting effects on mGlu2 versus effects on mGlu3 receptors, which is relevant for the potential use of subtype-selective agonists or allosteric activators. We addressed this issue using mGlu2 and mGlu3 receptor knock-out mice. We used mixed cultures of cortical cells in which astrocytes and neurons were plated at different times and could therefore originate from different mice. Cultures were challenged with NMDA for the induction of excitotoxic neuronal death. The mGlu2/3 receptor agonist, (Ϫ)-2-oxa-4-aminocyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY379268), was equally neuroprotective in cultures containing neurons from wild-type, mGlu2 ؊/؊ , or mGlu3 ؊/؊ mice. Neuroprotection was instead abolished when astrocytes lacked mGlu3 receptors, unless neuronal mGlu2 receptors were also absent. The latter condition partially restored the protective activity of LY379268. Cultures in which neurons originated from mGlu2 ؊/؊ mice were also intrinsically resistant to NMDA toxicity. In in vivo experiments, systemic administration of LY379268 protected striatal neurons against NMDA toxicity in wild-type and mGlu2 Ϫ/Ϫ mice but not in mGlu3 ؊/؊ mice. In addition, LY379268 was protective against nigrostriatal degeneration induced by low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine only in mice lacking mGlu2 receptors. We conclude that neuroprotection by mGlu2/3 receptor agonists requires the activation of astrocytic mGlu3 receptors, whereas, unexpectedly, activation of mGlu2 receptors might be harmful to neurons exposed to toxic insults.

The mGluR2/3 Agonist LY379268 Induced Anti-Reinstatement Effects in Rats Exhibiting Addiction-like Behavior

“…Male mGluR3 À / À and littermate control mice (Corti et al, 2007) were used in mouse self-administration experiments. Methods are fully described in Supplementary Information.…”

“…We first report on the effect of the mGluR2/3 agonist LY379268 in cue-induced reinstatement in addict-like vs non-addict-like rats and then present quantitative gene expression data on mGluR2 and mGluR3 following withdrawal from cocaine self-administration. To further dissect the role of these two different metabotropic glutamate receptors, we present data on cocaine self-administration, drug escalation, and cue-induced reinstatement in mGluR3 knockout (mGluR3 À / À ) mice (Corti et al, 2007). Motoric impairments preclude the use of mGluR2 knockouts for operant studies (Morishima et al, 2005).…”

Glutamate receptor mGlu2 and mGlu3 knockout striata are dopamine supersensitive, with elevated D2High receptors and marked supersensitivity to the dopamine agonist (+)PHNO

“…As reported previously, the mGlu3 receptor knockout mice were generated by Corti et al (2007), while the mGlu2 receptor knockout mice were obtained from Yokoi et al (1996). As documented earlier (Corti et al, 2007), the experiments with the mice were done according to the National Institutes of Health guidelines for animal care and use.…”

“…As documented earlier (Corti et al, 2007), the experiments with the mice were done according to the National Institutes of Health guidelines for animal care and use. The knockout mice had been individually genotyped for the mGlu2 and mGlu3 receptor genes by the polymerase chain reaction method.…”

“…The knockout mice had been individually genotyped for the mGlu2 and mGlu3 receptor genes by the polymerase chain reaction method. (Seeman et al, 2003), using striatal tissue from mice with mGlu2 and mGlu3 receptor knockouts (Corti et al, 2007).…”