Increased susceptibility of G-protein coupled receptor 6 deficient mice to MPTP neurotoxicity

The G-protein coupled receptor 6 (GPR6) is a constitutive active orphan GPCR which is predominantly expressed in striatopallidal neurons. GPR6 deficiency in mice may alter the susceptibility of the nigrostriatal dopaminergic system relevant for Parkinson's disease (PD). Here, we investigated the effect of GPR6 deficiency in mice on neurotoxicity induced by the dopaminergic neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). GPR6^-/-- and control mice were treated with MPTP (4×12.5mg/kg, i.p., 2h intervals) and analyzed after seven days. Striatal dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and 4-hydroxy-3-methoxyphenylacetic acid (HVA) concentrations were measured by HPLC. The number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNpc) was analyzed by immunohistochemistry. In a separate group of mice, MPP⁺ (500μM for 20min) was administered via an intrastriatal microdialysis probe to measure the MPP⁺-induced DA release. MPTP produced a significant reduction in striatal DA, DOPAC, HVA and an increase in dopamine turnover in control and GPR6^-/--mice. The MPTP-induced DA and HVA depletion was significantly more pronounced in GPR6^-/--mice. Consistently, the MPTP-induced reduction of TH-positive neurons in the SPpc was significantly higher in GPR6^-/--mice. Furthermore, the MPP⁺-induced dopamine release was significantly higher in GPR6^-/--mice. In conclusion, we showed that MPTP induces an enhanced dopaminergic neurodegeneration in GPR6^-/--mice indicated by alterations at the striatal and nigral level. We propose that GPR6 signaling is involved in the cascade of neurodegenerative events of the parkinsonian neurotoxin MPTP and suggest that pharmacological modulation of GPR6 might represent an entry point to further investigate GPR6 in PD.