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PUBLIC RELEASE DATE:
21-Aug-2014

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Contact: Phil Sahm
phil.sahm@hsc.utah.edu
801-581-2517
University of Utah Health Sciences

Mouse model for epilepsy, Alzheimer's gives window into the working brain

Mice carry a calcium protein marker

(SALT LAKE CITY)—University of Utah scientists have developed a genetically engineered line of mice that is expected to open the door to new research on epilepsy, Alzheimer's and other diseases.

The mice carry a protein marker, which changes in degree of fluorescence in response to different calcium levels. This will allow many cell types, including cells called astrocytes and microglia, to be studied in a new way.

"This is opening up the possibility to decipher how the brain works," said Petr Tvrdik, Ph.D., a research fellow in human genetics and a senior author on the study.

The research was published Aug. 14, 2014, in Neuron, a world-leading neuroscience journal. The work is the result of a three-year study involving multiple labs connected with The Brain Institute at the University of Utah. The lead author is J. Michael Gee, who is pursuing both a medical degree and a graduate degree in bioengineering at the university.

"We're really in the era of team science," said John White, Ph.D., professor of bioengineering, executive director of the Brain Institute and the study's corresponding author.

With the new mouse line, scientists can use a laser-based fluorescence microscope to study the calcium indicator in the glial cells of the living mouse, either when the mouse is anesthetized or awake. Calcium is studied because it is an important signaling molecule in the body and it can reveal how well the brain is functioning.

Using this method, the scientists are essentially creating a window into the working brain to study the interactions between neurons, astrocytes and microglia.

"We believe this will give us new insights for treatments of epilepsy and for new views of how the immune system of the brain works," White said.

About one-third of the 3 million Americans estimated to have epilepsy lack adequate treatment to manage the disease.

Describing a long-standing collaboration with fellow university researcher and professor of pharmacology and toxicology Karen Wilcox, Ph.D., White said, "We believe the glial cells are malfunctioning in epilepsy. What we're trying to do is find out in what ways astrocytes participate in the disease."

This research is expected to lead to new classes of drugs.

The ability to track calcium changes in microglial cells will also open up the possibility of studying inflammatory diseases of the brain. Every neurological disease, including Multiple Sclerosis and Alzheimer's, appears to include components of inflammation, the scientists said.

"Live imaging and monitoring microglial activity and responses to inflammation was not possible before," said Tvrdik, particularly in living animals. In the past, researchers studied post-mortem tissue or relied on invasive approaches using synthetic dyes.

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Authors of the article, "Imaging Activity in Neurons and Glia with a Polr2a-based and Cre-dependent GCaMP5G- IRES-tdTomato Reporter Mouse," are:

J. Michael Gee, Nathan A. Smith, Fernando R. Fernandez, Michael N. Economo, Daniela Brunert, Markus Rothermel, S. Craig Morris, Amy Talbot, Sierra Palumbos, Jennifer Ichida, Jason D. Shepherd, Peter J. West, Matt Wachowiak, Karen S. Wilcox, John A. White and Petr Tvrdik.

Mario R. Capecchi, Ph.D., distinguished professor of human genetics and biology and 2007 recipient of the Nobel Prize in physiology or medicine, also contributed to the paper.



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