Approximately 10,000 new cases of spinal cord injury (SCI) occur each year with peak incidence in adolescence and young adulthood. Chronic sequelae of this devastating disorder include skeletal muscle hypertonia, a manifestation of changes that occur in and around spinal motoneurons, causing the cells to discharge either spontaneously and/or exhibit an exaggerated response to segmental afferent input. Hypertonia is associated with spasticity, muscle spasms and secondary complications such as pain and soft tissue contractures. In the short-term, the goal of the proposed project is to identify and define, at the cellular level, changes that occur in motoneurons following SCI for the long-term purpose of developing a more clearly delineated basis for the development of pharmacologic agents to control hypertonia. A series of in vitro spinal cord slice preparation experiments is proposed that utilize intracellular (IC) techniques to identify changes in intrinsic firing properties of motoneurons following SCI (e.g., input resistance, rheobase current, functional threshold, stimulus current/firing frequency relationships, after hyperpolarization (AHP) features, and plateau potential characteristics). In addition, changes in two ionic currents (a nifedipine-sensitive calcium current, (ICa2+), and an apamin-sensitive calcium-dependent potassium current, IK(Ca2+)), that are known to be responsible for plateau potentials and the slow AHP, respectively, will be determined using voltage clamp techniques. Other studies will define anatomical changes that occur following SCI in horseradish-peroxidase- identified motoneurons and in central terminal branches of cutaneous afferents Another series of IC experiments will determine changes in sensitivities of motoneurons to various neurotransmitter species (serotonin, NMDA, GABA and glycine). Firing properties of segmental interneurons following chronic SCI will be determined using a multipolar electrode implanted in the turtle spinal cord. Receptor-binding studies (using 3H-strychnine as a ligand) will quantitate glycine receptors present in a mixed preparation of neuron membranes of the spinal cord. The development of hypertonia following SCI will be monitored and quantified with indwelling EMG electrodes in the external gastrocnemius and peroneus anterior muscles of an unrestrained animal. The preferred animal model for these studies of motoneuron behavior is the fresh water turtle which we have found to develop hypertonia following SCI. In this animal, motoneuron firing properties are strikingly similar to those of the cat. The advantage of the turtle, however, is. that viable adult neurons can be maintained for long recording sessions in vitro where it is possible to control the environment of the cells under study. The experiments outlined above represent a re-entry into neuroscience research as well as a progression in direction for the principal investigator: i.e., the proposed research will bridge the gap between the PI's earlier training in basic spinal cord physiology, neuromuscular adaptation, and her more recent clinical experience with SCI patients.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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University of Arizona
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Stauffer, E K; McDonagh, J C; Hornby, T G et al. (2007) Historical reflections on the afterhyperpolarization--firing rate relation of vertebrate spinal neurons. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 193:145-58
Gorman, R B; McDonagh, J C; Hornby, T G et al. (2005) Measurement and nature of firing rate adaptation in turtle spinal neurons. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 191:583-603
Stauffer, E K; Stuart, D G; McDonagh, J C et al. (2005) Afterhyperpolarization-firing rate relation of turtle spinal neurons. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 191:135-46
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Hornby, T G; McDonagh, J C; Reinking, R M et al. (2002) Electrophysiological properties of spinal motoneurons in the adult turtle. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 188:397-408
McDonagh, Jennifer C; Hornby, T George; Reinking, Robert M et al. (2002) Associations between the morphology and physiology of ventral-horn neurons in the adult turtle. J Comp Neurol 454:177-91
Hornby, T George; McDonagh, Jennifer C; Reinking, Robert M et al. (2002) Effects of excitatory modulation on intrinsic properties of turtle motoneurons. J Neurophysiol 88:86-97
Hornby, T George; McDonagh, Jennifer C; Reinking, Robert M et al. (2002) Motoneurons: A preferred firing range across vertebrate species? Muscle Nerve 25:632-48
Hornby, T G; McDonagh, J C; Reinking, R M et al. (2001) Associations between the passive, transitional, and active properties of turtle motoneurons. Acta Physiol Pharmacol Bulg 26:15-9
McDonagh, J C; Gorman, R B; Gilliam, E E et al. (1999) Electrophysiological and morphological properties of neurons in the ventral horn of the turtle spinal cord. J Physiol Paris 93:3-16

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