Objective: In a  toxicological model of mouse parkinsonism through chronic injection of MPTP, we examined whether the presence or absence of mGlu3 receptors affected neurodegeneration and neuroinflammation.
We also evaluated association in humans between polymorphic variants of GRM3 or GRM5 and Parkinson’s disease (PD) and L-DOPA-induced dyskinesias (LIDs).

Background: Type-3 metabotropic glutamate (mGlu3) receptors exert pleiotropic functions in the CNS. Presynaptic mGlu3 receptors inhibit glutamate release, whereas postsynaptic mGlu3 receptors boost mGlu5 receptors signaling. Activation of mGlu3 receptors in astrocytes stimulates the production of GDNF and TGF-β and drives microglia towards an anti-inflammatory phenotype.

Method: WT and mGlu3^-/- mice were chronically treated with MPTP (20 or 10 mg/kg, s.c., every other day). We analyzed dopamine (DA), DOPAC and HVA levels in the striatum at 10, 15 and 30 days through HPLC detection. We assessed nigro-striatal degeneration by immunohistochemical analysis of Tyrosine Hydroxylas in Substantia Nigra pars compacta (SNpc), and we evaluated microglia phenotype in the striatum. We are also examining the association between polymorphic variants of GRM3 (rs12704290, rs13242038, rs1468412, rs1527768, rs187993, rs1989796, rs2228595, rs2237562, rs2282966, rs2299225, rs274622, rs6465084, rs724226, rs802457, rs906415, and rs917071) or GRM5 (rs60954128 and rs3824927) and PD in a large cohort of patients.

Results: Chronic administration of MPTP in WT and mGlu3^-/- mice caused a substantial drop in DA, DOPAC and HVA levels in the striatum. At 10 and 30 days, the DA loss was significantly greater in mGlu3^-/- mice treated with 10 or 20 mg/kg respectively, as compared to their WT counterparts. mGlu3 receptor may have an anti-inflammatory activity, because of in mGlu3^-/- mice microglia M2 is less represented. These mice also showed lower levels of neurotrophic factors and a greater glial reaction. Moreover, ad interim analysis suggests an association between the GRM3 and GRM5 variants, PD and dyskinesias.

Conclusion: These findings suggest that mGlu3 receptors might shape the balance between neurodegeneration and neuroprotection in PD and might be targeted by therapeutic intervention.

References: .

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MDS Abstracts - https://www.mdsabstracts.org/abstract/mglu3-receptors-in-parkinsons-disease-as-a-candidate-target-for-neuroprotective-therapy-evidence-from-preclinical-studies-to-human-genetic/