Overexpression of neurotrophin-3 in skeletal muscle alters normal and injury-induced limb control

• Published in: Somatosensory & motor research 2001, Vol.18 (4), p.286-294
• Main Authors: Taylor, M D, Vancura, R, Williams, J M, Riekhof, J T, Taylor, B K, Wright, D E
• Format: Article
• Language: English
• Subjects: Animals; Extremities - innervation; Extremities - physiology; Gait; Gene Expression Regulation - physiology; Hindlimb - physiology; Mice; Mice, Transgenic; Muscle, Skeletal - metabolism; Myogenin - genetics; Nerve Crush; Neurons, Afferent - physiology; Neuroprotective Agents; Neurotrophin 3 - biosynthesis; Neurotrophin 3 - genetics; Postural Balance - physiology; Promoter Regions, Genetic - physiology; Proprioception - physiology; Proprioception Neurotrophin-3 Sciatic Functional Index Nerve Injury Gait Rotorod; Psychomotor Performance - physiology; Sciatic Nerve - injuries
• ISSN: 0899-0220; 1369-1651
• DOI: 10.1080/01421590120089668

Transgenic overexpression of neurotrophin-3 (NT-3) in mice increases the number of surviving proprioceptive sensory components, including primary sensory neurons, gamma motoneurons and muscle spindles. The numbers of surviving alpha motoneurons are not affected by NT-3 overexpression (Wright et al., Neuron 19: 503- 517, 1997). We have assessed the consequences NT-3-stimulated increase in the proprioceptive sensory system by measuring locomotive abilities of mice that overexpress NT-3 in all skeletal muscles ( myo/NT-3 mice). In adulthood, one myo/NT-3 transgenic line continues to express NT-3 at high levels in muscle and maintains a hypertrophied proprioceptive system (high-OE myo/NT-3 mice). Compared to wildtypes, high-OE myo/NT-3 mice have nine times the amount of NT-3 protein in the medial gastrocnemius at six weeks of age. Although appearing normal during ordinary activity, high-OE myo/NT-3 mice display a distinct clasping phenotype when lifted by the tail. High-OE myo/NT-3 mice show severe locomotor deficits when performing beam walking and rotorod testing. These mice also demonstrate aberrant foot positioning during normal walking. However, following sciatic nerve crush, overexpression of NT-3 prevents further abnormalities in paw positioning, suggesting NT-3 may attenuate sensorimotor deficits that occur in response to sciatic nerve injury. Our results suggest that increases in proprioceptive sensory neurons, spindles and gamma motoneurons, along with continued postnatal NT-3 overexpression in muscle significantly disrupt normal locomotor control. Importantly, however, NT-3 may lessen initial deficits and thus improve functional recovery after peripheral nerve injury, suggesting these mice may serve as a good model to study NT-3's role in neuroprotection of proprioceptive afferents.