Neurotrophins, such as nerve growth factor, have been shown to function during development particularly as survival factors but also as factors involved in differentiation and axon growth. However, both the neurotrophins themselves, NGF, BDNF, NT-4/5 and NT-3 and their high affinity receptors (trkA, trkB and trkC) continue to be expressed post-natally suggesting that their function goes far beyond their role in development. We propose to study their role in modulating synaptic transmission in the neonatal rat spinal cord. This preparation has the advantage of preserving much of the intrinsic spinal cord circuitry and therefore a considerable amount of normal function. It also has the advantage of being able to activate motoneurons via 2 different monosynaptic pathways (from the segmental dorsal root and the descending ventrolateral fasciculus) that have been very revealing in studies from this laboratory that prompt the present proposal. Three general types of experiments are proposed. The first group of experiments is concerned with the mechanism by which neurotrophins potentiate synaptic transmission in neonatal rat motoneurons. Specifically, we are aiming to provide further proof that a postsynaptic mechanism involving NMDA receptors is involved in potentiating the monosynaptic EPSP. The second group of experiments is focused on the relationship between neurotrophin- and activity- based potentiation of transmission in the mammalian spinal cord. The third group of experiments probes the functional effects of neurotrophins in development of this reflex pathway and in modulating rhythmic output from the spinal cord as is used in stepping. In addition to the developmental implications, these studies have application to central sensitization mechanisms known to be a factor in persistent pain states and to spinal cord repair mechanisms given the role of neurotrophins such as those used here (NT-3, BDNF) in encouraging elongation of damaged central axons.
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