The long-term objective of this research is to identify and study principles of organization in vertebrate CNS local synaptic circuits. The principles and events that contribute to the expression of local circuit plasticity remain controversial. A major impediment to advances in these areas of investigation has been in the accessibility of well defined cortical circuitry. However, the vertebrate olfactory bulb has been developed and documented as a viable model system for examining general principles of CNS structure and function. Also, the availability of a murine mutant that loses all olfactory bulb mitral cells during early adulthood greatly facilitates the investigation of plasticity. The current research proposal will utilize this system to examine organizational principles and the expression of plasticity in the adult CNS. Specific testable hypothesis include: 1) Normally quiescent developmental signals can be reactivated in the adult to promote plasticity and the stabilization of new synaptic circuits. 2) Plasticity is determined only in part by mechanisms intrinsic to denervated cells. Of comparable importance is the availability of synaptic sites on new target cells and their capacity to form pre- /postsynaptic specializations. 3) Plasticity is not a property unique to the local circuits of the olfactory bulb. Comparable reorganization may be identified in selectively denervated neocortical regions. The techniques to be employed include light and electronmicroscopy golgi studies, quantitative stereological electronmicroscopy, and light microscopy assessment of retrogradely transported tracers. The results will be important for understanding the organization ad plasticity of local circuits. Also, the results will provide important information on human disease states with demonstrable involvement of olfactory system circuitry including epilepsy and Alzheimer's dementia.
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