TRANSMISSION MODES AND THEIR MEDIATORS IN MOTONEURONS

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The long range objective of this project is to understand the mechanism of action of transmitters and/or modulators involved in synaptic transmission to and from motoneurons (MNs) and interneurons in the spinal cord. Three types of synaptic potentials and their putative transmitters were identified for the first time in the rat MNs during this grant period. Studies proposed here will address the cellular mechanisms underlying the actions of putative transmitters responsible for generating the fast and slow excitatory postsynaptic potentials (EPSPs) and the intracellular signal transduction associated with the activation of appropriate receptors by these transmitters. Current/voltage or whole-cell-patch recordings will be obtained from MNs and interneurons visualized in thin (120-150 mum) spinal cord slices from young and neonate rats. The proposed study has the following major objectives. First, the ionic mechanism underlying the glutamatergic EPSP will be investigated. The contribution of Na, K and Ca ions to the synaptic current and current induced by glutamate will be ascertained. The role of Ca ions in N-methyl-D-aspartate (NMDA) receptor- mediated responses will be evaluated. Second, the type(s) of K current responsible for the slow EPSP and the slow depolarization induced by putative transmitters including thyrotropin-releasing hormone (TRH) and 5- HT will be characterized. Third, the hypothesis that the closure of K channels by 5-HT and TRH is linked to the inositol triphosphate/diacylglycerol-protein kinase C (PI-KC) system will be evaluated by analyzing the dose-effects of PI-KC activators phorbol esters and diacylglycerol analogs on the K current determined in the Objective 2. Fourth, the electrical membrane properties of spinal interneurons, in particular, the intermediate nucleus interneurons and interneurons mediating a recurrent inhibitory postsynaptic potential will be characterized. The transmitter and receptor involved in afferent transmission to spinal interneurons will be determined. Fifth, the interaction between spinal interneurons and MNs will be evaluated with respect to the mode of transmission and the nature of transmitter. Clarifying the mechanism of action of putative transmitters and the role of intracellular second messengers is central to a better understanding of information processing in the MNs and interneurons. Further, this information should contribute to our knowledge with respect to transmitter related motoneuron disorders and to the rational design of drugs aimed at alleviating certain neuromuscular disorders.