The Effects of Exercise on Synaptic Stripping Require Androgen Receptor Signaling

Following peripheral nerve injury, synapses are withdrawn from axotomized motoneurons. Moderate daily treadmill exercise, which promotes axon regeneration of cut peripheral nerves, also influences this synaptic stripping. Different exercise protocols are required to promote axon regeneration in male and female animals, but the sex requirements for an effect of exercise on synaptic stripping are unknown. In male and female C57BL/6 mice, the sciatic nerve was transected in the mid-thigh. Mice were then exercised five days per week for two weeks, beginning on the third post-transection day. Half of the exercised mice were trained by walking slowly (10 M/min) on a level treadmill for one hour per day (continuous training). Other mice were interval trained; four short (two min) sprints at 20 M/min separated by five minute rest periods. A third group was untrained. The extent of synaptic contacts made by structures immunoreactive to vesicular glutamate transporter 1 and glutamic acid decarboxylase 67 onto axotomized motoneurons was studied in confocal images of retrogradely labeled cells. Both types of presumed synaptic contacts were reduced markedly in unexercised mice following nerve transection, relative to intact mice. No significant reduction was found in continuous trained males or interval trained females. Reductions in these contacts in interval trained males and continuous trained females were identical to that observed in untrained mice. Treatments with the anti-androgen, flutamide, blocked the effect of sex-appropriate exercise on synaptic contacts in both males and females. Moderate daily exercise has a potent effect on synaptic inputs to axotomized motoneurons. Successful effects of exercise have different requirements in males and females, but require androgen receptor signaling in both sexes.