TRANSMISSION MODES & THEIR MEDIATORS IN MOTONEURONS

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The long range objective of this project is to improve understanding of the pathways, transmitters and transmitter mechanisms by means of which impulse is transmitted from the presynaptic inputs to the motoneurons (MN's). Thin (500 mum) transverse spinal cord slices with their corresponding dorsal and ventral rootlets will be obtained from thoracolumbar segments of neonatal (12-18 days old) rat spinal cord and maintained in an organ bath. Intracellular recordings will be made from antidromically identified MN's. The conduction velocity of antidromic spikes will be calculated to further establish that the neuron in question is a MN. First, the passive and active membrane properties of alpha and gamma MN's will be characterized. Second, synaptic potentials will be induced from MN's by either stimulation of dorsal rootlets with a bipolar electrode or by focal stimulation 100-200 mum away from the impaled NM. The waveform, time course, input resistance change, reversal potential and the ionic mechanism of evoked synaptic potentials will be analyzed. Third, as our preliminary results have shown that both depolarizing and hyperpolarizing synaptic potentials with a time course of seconds to minutes can be evoked from MN's the electrophysiological characteristics of these slow potentials will be investigated. Fourth, the nature of transmitters responsible for the fast and slow synaptic potentials will be systematically analyzed using pharmacological antagonists to known and putative transmitters including excitatory and inhibitory amino acids, biogenic amines and peptides. Lastly, endogenous substances which are likely to serve as transmitters for the fast and slow synaptic potentials such as glutamate, aspartate, peptides (substance P, thyrotropin releasing hormone, enkephalins, etc.) and amines (norepinephrine, epinephrine, serotonin, etc.) will be applied to MN's by either superfusion or pressure ejection to determine whether or not these compounds mimic the fast and slow synaptic potentials. This proposal constitutes the first systematic attempt to define and characterize for the MN's the various transmission modes and their chemical mediators. This knowledge is central to our understanding of the function and dysfunction of the spinal cord and for the design of drugs in the treatment of many neurological disorders of the spinal cord; eg. the projected study may clarify the mechanism underlying thyrotropin releasing hormone therapy of amyotrophic lateral sclerosis and help developing better drugs or therapeutic regimens.