By Manoj Kumar, Ph.D.
The existence of zinc ions in the brain has been known for decades. Zinc ions help neurons to communicate with one another at neuron junctions called synapses and regulate sensory information processing in the brain. Changes to the amount of zinc ions at the synapses have been linked to numerous neurological diseases, such as stroke, epilepsy, depression, Alzheimer’s disease, and hearing disorders.
An illustration of the zinc ion-sensing mechanism of FRISZ (Far-Red Fluorescent Indicator for Synaptic Zinc). Credit: Wu and Kumar et al., Science Advances.
Although the importance of zinc in the brain has been widely known, because of the lack of sophisticated technology it had not been possible to visualize how zinc ions are being released at the synapses and mediate its actions in the brain. Now, however, by utilizing genetic, molecular, and imaging techniques, we have engineered and validated a technology that will allow the biomedical field to visualize and record zinc ion activity in the brain in real-time in acute brain-slice preparations and in non-anesthetized animals. We published our findings in Science Advances in March 2023.
We engineered a zinc-sensitive fluorescent protein called Far-Red Fluorescent Indicator for Synaptic Zinc (FRISZ). Next, we genetically modified FRISZ and packed it with viral vectors to express FRISZ over the outer cell membranes of brain neurons. Upon activation by zinc release at the neuron synapses during neurotransmission, FRISZ fluoresces sufficient brightness to be detected by sophisticated microscopes, providing a direct, robust measure of zinc signal intensity and location.
Next, we validated FRISZ to visualize zinc release in the auditory cortex, the brain region where sound information gets processed. In acute brain slices, electric stimuli elicit a robust increase in FRISZ fluorescence that was reduced with the application of a chemical compound that temporarily mops up zinc ions from the synapses. Similarly, in non-anesthetized mice, the presentation of sounds of different volumes elicits a robust increase in FRISZ fluorescence signal in the auditory cortex. Our study establishes a novel, genetically encoded technology for studying the roles of zinc ions in the nervous system.
Manoj Kumar, Ph.D., is a research assistant professor in the department of otolaryngology at the University of Pittsburgh. Kumar’s 2022 Emerging Research Grant is generously funded by Royal Arch Research Assistance, renewed for a second year in 2023.
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