Substance P neurons sprout in the cervical spinal cord of the wobbler mouse: a model for motoneuron disease.

The mutant mouse, wobbler, possesses a recessively inherited degeneration of motoneurons and other ventral horn cells in the cervical spinal cord, and therefore it has been proposed as an animal model of human motoneuron disease. Affected mice have been identified by behavioral tests that also determined the extent of the motor deficit. The results from these tests were combined and used to define distinct stages of the disease process that could then be correlated histochemically with the amount of acetylcholinesterase (AChE) staining in the cervical spinal cord. AChE is used as a marker for cholinergic neurons and is known to hydrolyze the neuropeptide modulator substance P (SP). SP, a peptide neuromodulator of primary afferent transmission in the dorsal horn, excites motoneurons in the ventral horn, and may possess secondary functions in neuronal maintenance. Therefore, the levels of immunoreactive (IR) SP and AChE were examined in an attempt to determine the possible interaction between these factors in motoneuron degeneration. By enzyme histochemistry, the cervical spinal cord, taken from wobbler mice at behaviorally identified stages of the motor deficit, exhibited decreased levels of AChE throughout the ventral horn. The decrease detected in the AChe staining intensity was linear and correlated with the decrease in the number of AChE-positive cells in the ventral cervical spinal cord, as the motor deficit progressed. Presumably, the continual decrease in AChE staining represents the degeneration of cholinergic perikarya and neuronal processes in the ventral horn as the motoneuron disease proceeds. At two well-established stages of the motor deficit, the amount of immunoreactive SP increased in the ventral horn compared with the control mice. The elevated levels of immunoreactive SP suggest sprouting may have occurred preceding, or in response to, the motoneuron degeneration. Several additional hypotheses are discussed in respect to phenomena that might contribute to the increase of immunoreactive SP in the degenerating ventral horn of the wobbler mouse.