Presynaptic calcium channels play a critical role in the communication of neurons with other tissues, and with each other. These molecular complexes, by undergoing voltage-dependent conformational changes, serve as literal gatekeepers to the final common biochemical pathway of neurotransmission for a wide variety of transmitters. They have also been implicated in pathologic processes ranging from paraneoplastic disease to neurologic injury secondary to cerebral ischemia. In light of the importance of the channels to normal neurophysiology and to neuropathologic conditions, a method to evaluate then in vivo could provide a valuable window into synaptic events that regulate and alter neurotransmission. The goal of this project is to study the feasibility of quantitatively assessing regional synaptic density in the living brain, while helping to lay the basic groundwork necessary to achieving quantitative imaging of presynaptic calcium channels in vivo. In addressing those problems, this proposal relates to the purpose of the Exploratory/Developmental (R21) Grant Program in several ways, including undertaking innovative research directions requiring preliminary testing, as well as developing new techniques and methods, to create tools with which to examine functional and dysfunctional brain tissue.
A specific aim of this proposal is to test the feasibility of what would be an almost immediate area of practical application for this work - the use of radioligands of N-type and P/Q-type calcium channels, coupled with high-resolution imaging technology, to noninvasively quantify the distribution of synaptic density in humans and animals undergoing synaptic loss associated with neurodegeneration. Our longer-term goal is to make ligands with affinities dependent upon whether the channels are in opened or closed conformation, thus serving as a molecular handle by which to directly visualize, and eventually modulate, synaptic activity. Another specific aim is prompted by the understanding that the likelihood of these goals being satisfactorily accomplished will be enhanced by developing methods to increase transport of the channel ligands across the blood-brain barrier. A possible peripheral benefit of this work lies in its potential to bring us closer to an effective CNS delivery system for calcium channel antagonists which are under clinical development as therapeutic agents.
