The experiments proposed in this project will elucidate important relationships between ligand binding site markers of cholinergic or dopaminergic neurons and the integrity and density of their terminals in the brain. We will seek to distinguish those markers that respond dynamically to perturbations in synaptic activity from markers whose expression appears related only to the survival of intact presynaptic nerve endings. The former may be of utility in elucidating regulatory responses to disease or following treatment, but will not serve as reliable quantitative markers of neuronal density. Markers satisfying the latter criterion are well-suited to the prospective analysis of disease and therapeutic interventions in neurodegenerative disorders, potentially providing objective measures of progression or response. The capability to determine such markers in noninvasive clinical settings, with the use of emission tomographic imaging, may ultimately permit detailed analyses of neuronal survival and death not previously possible. Our hypotheses are focused on the study of radioligand binding sites located on the membranes of synaptic vesicles, specific to cholinergic or to monoaminergic neurons. The ligands [3H]vesamicol and [3H]methoxytetrabenazine will be applied to the evaluation of these neuronal populations, respectively. We will compare the neurobiologic expression and regulation of these binding sites with additional measures of cell membrane transport sites for the presynaptic uptake of choline or of dopamine. Regulatory changes in the activities of these latter sites are well-known in the case of cholinergic neurons, and are potentially present in dopaminergic nerve terminals as well. Our experimental design will involve the use of chronic drug administration in animals to produce alterations in synaptic activity by potentiating or inhibiting neurotransmission. Under these conditions, regulatory modulation in neurotransmitter numbers are known to occur, permitting parallel documentation of the altered state of synaptic activity. We will then determine the possible presence of changes in the synaptic vesicle and presynaptic membrane uptake sites. Comparison of the above results of drug challenges and those following selective brain lesions, resulting in cortical cholinergic deficits or in striatal dopaminergic deficits, will be make with ligand binding markers in postmortem brain samples from subjects with Alzheimers's and Parkinson's diseases. Combined, these results will enhance understanding of the relateive contributions of neuronal loss and of secondary regulatory responses in these idiopathic disorders. Future clinical research studies, based on carefully-chosen markers of synaptic integrity, will then be possible.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG008671-08
Application #
5204617
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
1996
Total Cost
Indirect Cost
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