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Principal Investigator/Program Director (Last, first, middle): Alford, Simon, T PHS 398/2590 (Rev. 05/01) Page _1___ Continuation Format Page

Summary: Principal Investigator/Program Director (Last, first, middle): Alford, Simon, T
PHS 398/2590 (Rev. 05/01) Page _1___ Continuation Format Page
a. Specific Aims
Modulation of the efficacy of synaptic transmission is a key component of neural plasticity. Presynaptic
receptors are known to depress neurotransmitter release profoundly. We have demonstrated that G protein-
coupled receptors (eg. 5-HT receptors) inhibit synaptic transmission by an effect mediated directly at the core
complex for vesicle fusion. We hypothesize that the mechanism for this modulation is an alteration in fusion
pore dynamics as the synaptic vesicle releases transmitter. This modulation of fusion can have profoundly
different effects on nervous system plasticity than alterations in vesicle fusion probability. Indeed, this
incomplete fusion will conserve vesicles during repetitive activity, but it may also change the mode of synaptic
transmission by favoring different postsynaptic receptors with different affinities and different subsynaptic
locations. We seek to explore the mechanism by which G protein-coupled receptors modify synaptic vesicle
fusion and the subsequent effects on cleft neurotransmitter concentration and postsynaptic receptors activation.
Specific Aim 1. Probing the fusion pore with styryl dyes
We will use Styryl dyes (eg FM 1-43) to probe vesicle endocytosis, exocytosis and recycling. We have
previously demonstrated that these dyes can be used to monitor synaptic vesicle recycling in the intact lamprey
spinal cord and have shown that 5-HT causes trapping of FM dyes within synaptic vesicles while allowing the
simultaneous escape of neurotransmitter. In this aim we propose to use these dyes to probe synaptic vesicle
exocytosis or incomplete fusion by monitoring the ability of the dye to enter or exit fusing vesicles in the
presence and absence of exogenous 5-HT in the lamprey spinal cord. Using 5-HT to induce incomplete fusion


Source: Alford, Simon - Department of Biological Sciences, University of Illinois at Chicago


Collections: Biology and Medicine