The flow of electrical signals in every sensory system and throughout the nervous system is mediated by the secretion of neurotransmitter molecules from one neuron to another neuron, or to a muscle cell, at specialized regions called synapses. Control and regulation of secretion, or exocytosis, and subsequent activation of postsynaptic cells underlies much of the adaptive and modifiable behavior of the nervous system. Two striking examples of how external stimuli modify synaptic pathways are in the eye where light and dark profoundly influence signal transmission and in the hippocampus where repeated stimulation of inputs to a neuron can produce long term potentiation or depression of synaptic efficacy. In this proposal we will determine how calcium, an important controller of exocytosis, is regulated in rods and cones. Preliminary experiments have shown that control of calcium levels in cones is much faster than rods, consistent with the much faster cone responses. We will also examine the mechanism by which dopamine, a neuromodulator substance that rises during light-adaptation, reduces calcium levels in both rods and cones. Further experiments will be done to directly measure exocytosis optically and electrically using selective dyes and electrophysiological recordings from single rods and cones. In a collaborative study with Louis Reichardt, we will investigate how neurotrophins directly and quickly modify synaptic activity at newly formed nerve/muscle synapses from Xenopus spinal cord. We will determine the intracellular pathways and important molecular structures of the signalling molecules. Additionally, the techniques and instrumentation we have developed to measure calcium concentrations and exocytosis in synaptic terminals will be applied to measure these features of synaptic function in two different preparations used by two other investigators on this program project. All of these studies should yield valuable insights into how synaptic transmission is regulated and modified in the nervous system.
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