Mobile zinc is an important signaling ion in the brain, where it can be found concentrated in certain neurons in the cerebral cortex. Zinc has been shown to modulate long-term potentiation at synapses and is thought to play a role in memory and learning. In healthy individuals, the flow of zinc between neurons and its subsequent intracellular trafficking is tightly regulated but poorly understood. Dysregulation of zinc transpot networks can affect brain excitability. Disruptions in zinc homeostasis have been implicated in a number of pathologies, including Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), epilepsy, and ischemia. The biochemical basis for zinc's role in these diseases is largely unknown. An improved understanding of how zinc moves into and through neuronal cells will offer valuable insight into how the brain works and might provide clues about the molecular basis underlying these debilitating neurodegenerative diseases. From this information, it may be possible to design new therapeutic strategies. To accomplish these goals, new tools to study zinc dynamics in live cells will be developed. Specifically, a family of multicolor fluorescent sensors with similar zinc binding properties will be synthesized and characterized. The probes will be attached to cellular homing molecules that will direct each probe to a certain compartment or substructure of a cell. The entire set of probes will be applied to a tissue sample and imaged simultaneously. In this manner it will be possible to observe zinc dynamics at multiple organelles over the same timecourse. Application of such probes in neuronal tissue, for example, will allow for the tracking of zinc transport during excitatory event. In this way, new experiments can be designed to rigorously characterize the role of zinc in cell-to-cell communication and in healthy and disease states. The tools developed in the study will be broadly applicable for imaging zinc dynamics in other tissues throughout the body including the mammary gland, pancreas, and prostate, where zinc has been implicated in multiple disease pathologies, such as prostate cancer. In separate but related work, experiments will be performed to test the hypothesis that odor learning depends on synaptic release of zinc in the olfactory bulb. Synaptically released zinc is closely associated with information storage in some parts of the brain by altering plasticity-how the activity of a synapse changes over time in response to a stimulus. Curiously, the only synapses in the olfactory bulb known to show plasticity also have some of the highest concentrations of zinc. Chelators, which are molecules that sequester zinc tightly, and fluorescent zinc indicators will be used to study the role of zincin generating plasticity. Because these synapses appear to be engaged in challenging sensory discriminations, tests will be conducted to probe how zinc release is affected in the olfactory bulb after learning a difficult odor discrimination task. From the data collected in these experiments, one will be able to determine if the patterns of zinc release change upon odor-mediated learning and draw conclusions about the importance of zinc in modulating olfaction.
Zinc is a signaling ion in some neurons and plays an important but poorly understood role in memory and learning. Disruptions to the movement of zinc in the brain have been implicated in a number of pathologies, including Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), epilepsy, and ischemia. Novel tools will be developed to study how zinc moves in cells so that new experiments can be designed to understand the biochemical basis for these observations and design new treatments.
|Goldberg, Jacob M; Lippard, Stephen J (2017) Challenges and Opportunities in Brain Bioinorganic Chemistry. Acc Chem Res 50:577-579|
|Kalappa, Bopanna I; Anderson, Charles T; Goldberg, Jacob M et al. (2015) AMPA receptor inhibition by synaptically released zinc. Proc Natl Acad Sci U S A 112:15749-54|