In broad terms, the overall goal of this research program is to understand the mechanisms of neurotransmission in the vertebrate retina. More specifically, this research program will provide new information about intrinsic, Ca2+-dependent mechanisms that regulate synaptic vesicle dynamics in retinal bipolar cells. These neurons provide the major conduit through which visual information is relayed across the vertebrate retina. Bipolar cells can release a brief burst of neurotransmitter, to signal contrast, and they cn release neurotransmitter continuously, to provide an on-going read-out of luminance. Yet, little is known about the molecular mechanisms that support these behaviors, particularly at the level of synaptic vesicle dynamics. This research program is designed to provide this essential information for the rod-driven bipolar cell. First, we examine two Ca2+-interacting proteins of rod bipolar cells, the plasma membrane Ca2+ ATPase, a major regulator of bipolar cell intraterminal Ca2+, and CaBP5, a Ca2+-binding protein of poorly-understood function required for normal rod-pathway signaling. Each has the potential to modulate synaptic vesicle dynamics via local modulatory actions at or near the fusion machinery. In addition, they may modulate synaptic vesicle dynamics via the regulation of bulk intraterminal Ca2+. We will use a powerful combination of biophysical, pharmacological and molecular approaches, including the use of genetically-engineered mice, to determine the roles that these proteins play in the modulation of synaptic vesicle dynamics and the determination of synaptic gain. We will employ a similarly powerful combination of techniques to examine the roles of Munc13 and downstream Ca2+ signaling pathways in synaptic vesicle priming and short-term plasticity. Results of the proposed research program will yield new, molecular-level information about intrinsic Ca2+-dependent mechanisms that support continuous release and preserve synaptic gain in the bipolar cell synaptic terminal. In addition, results of this research program will shed light on general presynaptic mechanisms that mediate short-term adaptive changes throughout the nervous system. Finally, given the central role of bipolar cells in several strategies of vision restoratio, knowledge of the molecular mechanisms underlying the intrinsic Ca2+-dependent regulation of synaptic vesicle dynamics may suggest new targets of therapeutic intervention that will help improve visual outcomes.
Results of this research program will enhance our understanding of how we see, providing information for the development of new treatments that will restore vision or prevent its further loss. In addition, it will provide general information aout how neurons communicate that is critical for understanding brain diseases such as epilepsy, dementia and schizophrenia.
|Liu, Xiaoqin; Heidelberger, Ruth; Janz, Roger (2014) Phosphorylation of syntaxin 3B by CaMKII regulates the formation of t-SNARE complexes. Mol Cell Neurosci 60:53-62|
|Frazao, Renata; McMahon, Douglas G; Schunack, Walter et al. (2011) Histamine elevates free intracellular calcium in mouse retinal dopaminergic cells via H1-receptors. Invest Ophthalmol Vis Sci 52:3083-8|
|Wan, Qun-Fang; Heidelberger, Ruth (2011) Synaptic release at mammalian bipolar cell terminals. Vis Neurosci 28:109-19|
|Wan, Qun-Fang; Zhou, Zhen-Yu; Thakur, Pratima et al. (2010) SV2 acts via presynaptic calcium to regulate neurotransmitter release. Neuron 66:884-95|
|Duncan, Gabriel; Rabl, Katalin; Gemp, Ian et al. (2010) Quantitative analysis of synaptic release at the photoreceptor synapse. Biophys J 98:2102-10|
|Curtis, L; Datta, P; Liu, X et al. (2010) Syntaxin 3B is essential for the exocytosis of synaptic vesicles in ribbon synapses of the retina. Neuroscience 166:832-41|
|Melicoff, Ernestina; Sansores-Garcia, Leticia; Gomez, Alejandra et al. (2009) Synaptotagmin-2 controls regulated exocytosis but not other secretory responses of mast cells. J Biol Chem 284:19445-51|
|Innocenti, Barbara; Heidelberger, Ruth (2008) Mechanisms contributing to tonic release at the cone photoreceptor ribbon synapse. J Neurophysiol 99:25-36|
|Wan, Qun-Fang; Vila, Alejandro; Zhou, Zhen-Yu et al. (2008) Synaptic vesicle dynamics in mouse rod bipolar cells. Vis Neurosci 25:523-33|
|Heidelberger, Ruth (2007) Mechanisms of tonic, graded release: lessons from the vertebrate photoreceptor. J Physiol 585:663-7|