Effect of Oestrogen Receptors on Brain NMDA Receptors of 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Mice

Parkinsons disease (PD) is characterised by the loss of nigrostriatal dopamine (DA) neurones and glutamate overactivity. There is substantial evidence to suggest that oestrogens prevent or delay the disease. 17 beta-oestradiol has neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD and modulates brain NMDA receptors. In MPTP-lesioned mice, oestrogen receptor (ER)alpha and ER beta are important in 17 beta-oestradiol-induced neuroprotection. To evaluate the role of ERs in the response of NMDA receptors to lesion, we compared wild-type (WT) with ER knockout (KO) C57Bl/6 male mice that received 7, 9 or 11 mg/kg of MPTP. These mice were also treated with MPTP (9 mg/kg) and 17 beta-oestradiol. [3H]Ro 25-6981 specific binding autoradiography was used to label NMDA receptors containing NR2B subunits. In the frontal and cingulate cortex and striatum, vehicle-treated WT mice had higher [3H]Ro 25-6981 specific binding compared to ERKO mice. Cortical [3H]Ro 25-6981 specific binding decreased with increasing doses of MPTP in WT and ERKO alpha but not ERKO beta mice, whereas a dose-related decrease was only observed in the striatum of WT mice remaining low in ERKO alpha and ERKO beta mice. No effect of 17 beta-oestradiol treatment in intact or MPTP-lesioned mice of all three genotypes was observed in the cortex, whereas it increased striatal specific binding of intact ERKO beta and MPTP-lesioned WT mice. Striatal [3H]Ro 25-6981 specific binding positively correlated with striatal DA concentrations only in WT mice. MPTP and 17 beta-oestradiol treatments had more limited effects in the hippocampus. Only in the CA3 and dentate gyrus did vehicle and 17 beta-oestradiol-treated ERKO alpha mice have higher [3H]Ro 25-6981 specific binding than WT and ERKO beta mice, whereas MPTP decreased this specific binding only in the CA1, CA2 and CA3 of ERKO alpha mice. Hence, brain NMDA receptors were affected by the deletion of ERs, which affect the response to MPTP and 17 beta-oestradiol treatments with brain region specificity.