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

Abstract

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+/-0.7s), and had longer stride lengths (hindlimb 7.3+/-0.1 vs. 6.8+/-0.1cm). 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+/-1.9s, 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.

Figure 1

Rotarod performance in gonadectomized male (black) and female (white) mice (n=13-15 per group). Overall rotarod performance (ORP) for saline- (clear) and MPTP-treated (shaded) for GDX+H mice (A) and GDX mice (C). Latency to fall off the rotarod at 12-26 rpm for saline- (squares) and MPTP-treated (circles) for GDX+H mice (B) and GDX mice (D). Bars with different letter subscripts are significantly different. Asterisks represent sex differences (p<0.05) within the same treatment group (MPTP or Saline). Abbreviations: GDX, gonadectomy; GDX+H, gonadectomy with hormone replacement.

Figure 2

Pole test performance in male (black bars) and female (white bars) mice (n=13-15 per group). Time to completely descend the pole for for saline- (clear) and MPTP-treated (shaded) GDX+H mice (Top) and GDX mice (Bottom). Bars with different letter subscripts are significantly different. Abbreviations: GDX, gonadectomy; GDX+H, gonadectomy with hormone replacement.

Figure 3

Stride length in male (black bars) and female (white bars) mice (n=13-15 per group). Hindlimb stride lengths for saline- (clear) and MPTP-treated (shaded) GDX+H mice (Top) and GDX mice (Bottom). Bars with different letter subscripts are significantly different. Abbreviations: GDX, gonadectomy; GDX+H, gonadectomy with hormone replacement.

Figure 4

Photomicrographs of TH-positive neurons in SNC of saline- (A) and MPTP-treated (B) mice. (C) Mean±SEM number of TH-labeled neurons in male (black bars) and female (white bars) mice (n=7-9/group) in SNC. There were no significant differences between groups. Scale bar =200um. Abbreviations: 3n, third cranial nerve; SNC, substantia nigra pars compacta; TH, tyrosine hydroxylase; VTA, ventral tegmental area.