West Virginia University neuroscientists have discovered a way to control how much zinc is released to specific locations in the brain. The essential mineral plays a major role in the organ’s function, including improving memory and lessening symptoms of some neurological disorders, but getting the right amount to the right place is key.
“Zinc is like a volume knob in many parts of the brain,” said Charles Anderson, assistant professor in the Department of Neuroscience and Rockefeller Neuroscience Institute with the WVU School of Medicine, who led the study which could provide a foundation for pharmaceutical developments to address a range of diseases.
“You can turn it a little bit up and a little bit down. The idea was that if we could find the drugs that control that last little bit of volume, we can selectively change certain connections in the brain that have zinc and the receptors that zinc acts on.”
The study, published in The Journal of Neuroscience, focuses on the zinc transporter protein ZIP12. Researchers were able to determine its presence in a specific part of the brain to affect synaptic activity — the way nerve cells communicate information.
Anderson said the finding is important because it helps researchers advance their understanding of the roles synaptic zinc plays in health and disease, and how molecular compounds can be used to change their strength.
“It’s basically a way to fine-tune synaptic transmission,” Anderson said.
Multiple studies have shown that zinc levels, as well as receptor sensitivity, in the brain determine the strength or weakness of synaptic connections. Additional research links altered synaptic zinc signaling to neurological conditions such as autism, schizophrenia and Alzheimer’s disease.
“There are several neurological conditions associated with changes in these zinc transporter proteins,” Anderson said. “For example, when we profile people who have schizophrenia versus healthy people, we find extra zinc transporters expressed in the brains of people with schizophrenia. If we could make a drug that reduces the function of that zinc transporter, that might help turn their system back down to the level of a healthy person.”
The work builds on Anderson’s longtime studies of how much zinc is released from one neuron to another, what it does and how long it lasts.
“These are three fundamental basic features of zinc signaling,” he said. “That gives us an outline of what’s possible when we think about how the brain could take advantage of the systems it can use to modulate strength.”
However, Anderson and his colleagues needed the tools to block and activate different parts of the zinc transporter system. That’s when they began screening a class of molecular compounds that interfere with the protein. Philip Bender, a WVU alumnus and postdoctoral research fellow from Morristown, New York, designed and performed experiments on brain tissue using the identified compounds to determine and measure how they changed synaptic function.
“The major importance of this study is the identification of a family of compounds which could potentially lead to therapeutics for a wide range of disorders, as the transporters that were targeted have tissue-specific functions,” Bender said.
Working with Anderson and Bender in the study were Abbey Manning, a doctoral student in the WVU School of Medicine; Benjamin Z. Mendelson, medical student in the WVU School of Medicine; Kaitlin Bainer, Rayli Ruby, Victoria R. Shifflett and Donald Dariano, doctoral students in the WVU School of Medicine; Bradley A. Webb, assistant professor in the WVU School of Medicine Department of Biochemistry and Molecular Medicine; and Werner J. Geldenhuys, professor in the WVU School of Pharmacy and School of Medicine.
Anderson said he hopes the findings provide a toolbox for scientists to better understand how the proteins contribute to brain function. He is also planning future studies to determine the role zinc plays in sensory processing, such as the ability to discriminate different sounds from each other, which is an important therapeutic consideration in neurological conditions.
