Preclinical and clinical study on type 3 metabotropic glutamate receptors in Parkinson's disease.

Metabotropic glutamate (mGlu) receptors are candidate drug targets for therapeutic intervention in Parkinson's disease (PD). Here we focused on mGlu3, a receptor subtype involved in synaptic regulation and neuroinflammation. mGlu3(-/-) mice showed an enhanced nigro-striatal damage and microglial activation in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Expression of genes encoding anti-inflammatory proteins and neuroprotective factors was reduced in the striatum of MPTP-treated mGlu3(-/-) mice. We also examined polymorphic variants of GRM3 (the mGlu3 receptor encoding gene) in 723 PD patients and 826 healthy controls. Two GRM3 haplotypes were associated with PD, and gene variants correlated with motor and non-motor signs. Interestingly, PD patients carrying each of the two haplotypes showed an impaired cortical plasticity in the paired associated stimulation paradigm of magnetic transcranial stimulation. These findings suggest that mGlu3 receptors are neuroprotective in mouse models of parkinsonism and shape mechanisms of cortical plasticity in PD.