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

Transgenic overexpression of neurotrophin-3 (NT-3) in mice increases the nu mber of surviving proprioceptive sensory components, including primary sens ory neurons, gamma motoneurons and muscle spindles. The numbers of survivin g alpha motoneurons are not affected by NT-3 overexpression (Wright et al., Neuron 19: 503-517, 1997). We have assessed the consequences NT-3-stimulat ed increase in the proprioceptive sensory system by measuring locomotive ab ilities of mice that overexpress NT-3 in all skeletal muscles (myo/NT-3 mic e). 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 we eks of age. Although appearing normal during ordinary activity, high-OE myo /NT-3 mice display a distinct clasping phenotype when lifted by the tail. H igh-OE myo/NT-3 mice show severe locomotor deficits when performing beam wa lking and rotorod testing. These mice also demonstrate aberrant foot positi oning during normal walking. However, following sciatic nerve crush, overex pression of NT-3 prevents further abnormalities in paw positioning, suggest ing NT-3 may attenuate sensorimotor deficits that occur in response to scia tic nerve injury. Our results suggest that increases in proprioceptive sens ory neurons, spindles and gamma motoneurons, along with continued postnatal NT-3 overexpression in muscle significantly disrupt normal locomotor contr ol. Importantly, however, NT-3 may lessen initial deficits and thus improve functional recovery after peripheral nerve injury, suggesting these mice m ay serve as a good model to study NT-3's role in neuroprotection of proprio ceptive afferents.