Estrogen receptors modulate striatal metabotropic receptor type 5 in intact and MPTP male mice model of Parkinson’s disease

• mGlu5 receptor specific binding is lower in dorsal compared to ventral striatum.
• mGlu5 receptor specific binding is similar in lateral compared to medial striatum.
• Striatal mGlu5 receptor binding is lower in ERKOα and ERKOβ compared to WT mice.
• Striatal mGlu5 receptor binding decreases in MPTP WT but not in ERKOα and ERKOβ mice.
• Estradiol modulates striatal mGlu5 receptors and BDNF in MPTP WT but not ERKO (α or β) mice.

Glutamate is the most important brain excitatory neurotransmitter and glutamate overactivity is well documented in Parkinson’s disease (PD). Metabotropic glutamate (mGlu) receptors are reported to interact with membrane estrogen receptors (ERs) and more specifically the mGlu5 receptor subtype. 17β-estradiol and mGlu5 antagonists have neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. We previously reported that ERα and ERβ are involved in neuroprotection following MPTP toxicity. The present study investigated the implication of ERs on the mGlu5 receptor adaptive response to MPTP toxicity in the brain of wild type (WT), ER knockout (ERKO)α and ERKOβ male mice. Autoradiography of [3H]ABP688 specific binding to striatal mGlu5 receptors showed a dorsal/ventral gradient similar for WT, ERKOα and ERKOβ mice with higher values ventrally. The lateral septum had highest [3H]ABP688 specific binding that remained unchanged in all experimental groups. ERKOα and ERKOβ mice had similarly lower striatal [3H]ABP688 specific binding than WT mice as measured also by Western blots. MPTP dose-dependently decreased striatal [3H]ABP688 specific binding in WT but not in ERKOα and ERKOβ mice; this correlated positively with striatal dopamine concentrations. A 17β-estradiol treatment for 10 days left unchanged striatal [3H]ABP688 specific binding of unlesioned mice of the three genotypes. 17β-estradiol treatment for 5 days before MPTP and for 5 days after partially prevented the mGlu5 receptor decrease only in WT MPTP mice and this was associated with higher BDNF striatal contents. These results thus show that in male mice ERs affect striatal mGlu5 receptor levels and their response to MPTP.