Spinal motoneurons are essential for all movements. Their excitability is highly dependent on input from axons that originate in the brainstem and release the monoamines serotonin and norepinephrine. These neuromodulators facilitate strong persistent inward currents (PICs) in the dendrites of motoneurons, which enhance the effectiveness of synaptic input by as much as 6-fold. The loss of monoaminergic input to the distal spinal cord after spinal cord injury should thus tend to render motoneurons non-excitable. Yet, if motoneurons are non-excitable, why do spinal cord injury patients often suffer from debilitating spasms due to the presence of hyperexcitable, long-lasting spinal reflexes? This paradox has largely been resolved by recent studies of motoneurons following chronic injury of the sacral spinal cord of the rat. The motoneurons caudal to the injury site slowly re-develop the capacity to generate PICs over several weeks. Spasms develop in the affected musculature in the tail with the same post-injury time course as this recovery of the PICs. Thus, the redevelopment of PICs plays a primary role in the generation of spasticity in chronic injury. The goals of this proposal are to investigate the mechanisms of the post-injury re-development of motoneuron PICs (Aims 1 and 2) and to explore the implications of these mechanisms for drugs that could control spinal spasticity (Aims 3 and 4). All studies use the rat sacral cord chronic injury model, with the Aims 1 to 3 using an in vitro preparation that allows intracellular recordings and Aim 4 using awake animals with spastic tails.
Aim 1 considers the likelihood that motoneurons slowly become supersensitive to monoamines, so that the low levels of monoamines that persist post-injury begin to again facilitate the motoneuron PIC.
Aim 2 focuses on analyzing injury-induced changes in dendritic distribution and density of the ion channels generating the PICs. Such changes would contribute to PIC redevelopment and supersensitivity.
Aim 3 considers whether monoamine actions on motoneurons occur via different receptor subtypes than on interneurons. Finally, Aim 4 investigates the effectiveness of subtype specific monoaminergic agents on spasticity in the tails of chronically injury rats. These studies will not only enhance the understanding of cellular mechanisms of spasticity in spinal injury, but will also provide a basis for development of new pharmacological agents for therapeutic control of spasticity in human patients. ? ?
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