Sex differences in motor behavior in the MPTP mouse model of Parkinson's disease

Sex differences in Parkinson's disease (PD) have been reported in humans and rodent models, with a higher incidence in men and increased severity in male rodents. The current study examined sex differences and the effects of gonadal steroid hormones in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse model of PD. Male (n = 51) and female (n = 50) mice were gonadectomized and received physiologic replacement with testosterone or estrogen (Experiment 1), or no hormones (Experiment 2). Two weeks later, mice received either MPTP (10 mg/kg per day for 5 days) or saline. Higher doses killed female mice. Mice were tested one week after MPTP for motor performance using rotarod, pole and gait tests. In hormone-treated mice, males significantly outperformed females in all three tests (p < 0.05). Compared with females, males had a greater overall rotarod performance (ORP: 1317.1 ± 98.3 vs. 988.1 ± 95.6), descended a pole faster (7.1 ± 0.6 vs. 9.6 ± 0.7 s), and had longer stride lengths (hindlimb 7.3 ± 0.1 vs. 6.8 ± 0.1 cm). By contrast, ovariectomized female mice receiving saline outperformed castrated males on the rotarod (1296.6 ± 83.3 vs. 811.2 ± 113.7, p < 0.05) and descended a pole faster (9.7 ± 2.0 vs. 15.6 ± 1.9 s, p < 0.05). MPTP significantly impaired ORP (p < 0.05) in hormone-treated males (703.7 ± 65.5) and females (432.8 ± 88.6, p < 0.05). After MPTP, stride length was selectively decreased in males (hindlimb 6.6 ± 0.1 cm, p < 0.05), and pole test performance was unimpaired in either sex. After gonadectomy, MPTP did not decrease motor performance in males (p > 0.05) but significantly reduced ORP in females (975.9 ± 110.3 vs. saline females, p < 0.05). Our results show that small, chronic doses of MPTP produce subtle, sexually-dimorphic impairments in motor performance, but without a loss of tyrosine hydroxylase-positive neurons in the substantia nigra. In gonadectomized mice, this sex difference is reversed.