This proposal is to study influences on synaptic strength in the spinal monosynaptic reflex pathway in rat hindlimb circuits. Particularly, the synapses between the Ia afferent fibers and the motoneurons change their behavior after nerve cut. The proposal addresses the questions whether the changes are (specific aim 1) due to changes in activity of the afferent fibers, (specific aim 2) due to changes in activity of the muscles, and/or (specific aim 3) due to changes in neurotrophin levels. The system lends itself to addressing such questions for several reasons, including: the accessibility of the postsynaptic neurons for recording excitatory post-synaptic potentials (EPSPs), divergence of afferent fibers from a given muscle to motoneurons innervating both the same (homonymous) and other (heteronymous) muscles, and effective separation of the elements of the circuit allowing independent manipulation at various points along it. Two approaches will be used to address the first specific aim, regarding the influence of changes in afferent activity in cut fibers on synaptic strength. The first approach involves comparison of EPSPs generated by cut afferent fibers that are silent vs. those that fire spontaneously, and the second approach involves measurement of EPSPs generated by afferent fibers electrically stimulated over several days after nerve cut. The hypothesis is that afferent activity normally prevents increased synaptic strength, which is then released when the activity is decreased by nerve cut. In addition, levels of neurotrophins will be tested in the associated tissues to assess their possible involvement.
Specific aim 2, concerning the effect of muscle activity on synaptic strength, will be tested by paralyzing a peripheral muscle using tetrodotoxin applied to its efferent nerve, then stimulating to activate the muscle. Such stimulation should prevent the increase in synaptic strength associated with the paralysis, if muscle activity is an important factor. Again, levels of neurotrophic factors will be assessed for possible involvement.
Specific aim 3 will more directly assess the influence of neurotrophic factors in the target muscles on central synaptic strength by manipulating the levels of endogenous factors by sequestration using receptor complexes. The hypothesis will be tested that the reduction in availability of these factors from the muscle when the nerve is cut results in an increase in synaptic strength (that the neurotrophic factors normally prevent such an increase in synaptic strength).
| Bichler, Edyta K; Nakanishi, Stan T; Wang, Qing-Bo et al. (2007) Enhanced transmission at a spinal synapse triggered in vivo by an injury signal independent of altered synaptic activity. J Neurosci 27:12851-9 |
| Riley, Catherine P; Cope, Timothy C; Buck, Charles R (2004) CNS neurotrophins are biologically active and expressed by multiple cell types. J Mol Histol 35:771-83 |
| Buck, C R; Seburn, K L; Cope, T C (2000) Neurotrophin expression by spinal motoneurons in adult and developing rats. J Comp Neurol 416:309-18 |
