Altered neurons fluoresce as they fire, with potential to speed drug development

Hoping to gain new insight on how signals travel in the brain and how learning alters neural pathways, researchers at Harvard University (Cambridge, MA) have created genetically altered neurons that light up as they fire—a creation that could lead to faster drug development.

The work—led by Adam Cohen, John L. Loeb Associate Professor of the Natural Sciences—involved using a gene from a Dead Sea microorganism to produce a protein that, when exposed to the electrical signal in a neuron, fluoresces, allowing researchers to trace the propagation of signals through the cell.

Doing so enabled the researchers to see how these signals spread through the neuronal network, says Cohen. They can now study the speed at which the signal spreads, and if it changes as the cells undergo changes. The discovery may lead to being able to study how these signals move in living animals someday, he says.

To create the fluorescing neurons, Cohen and his team infected brain cells that had been cultured in the lab with a genetically altered virus that contained the protein-producing gene. Once infected, the cells began manufacturing the protein, allowing them to light up.

A neuron has a membrane around the whole cell—much like a wire and insulation—except in a neuron the membrane is an active substance unlike that of other cell types, says Cohen. When a neuron fires, the voltage reverses for a very short time--about one one-thousandth of a second, he says. The brief voltage spike then travels down the neuron and activates other neurons downstream. The team's protein sits in the membrane of the neurons so as that pulse washes over the proteins, they light up, giving them an image of the neurons as they fire, he adds.

The research shows promise in understanding how electrical signals move through the brain as well as other tissues, particularly when it comes to the development of new drugs or other therapies, says Cohen.

Many drugs target ion channels—proteins that govern heart and brain activity—and the current method for testing compounds designed to activate or inactivate a particular ion channel involves culturing the cell, testing it with an electrode, and then adding the drug to see what happens, which can take an hour or two for each data point, he says. However, the team's optical microscope method enables them to test the efficacy of a drug on a cell in a few seconds. Instead of testing one compound or 10 compounds, they can try to test thousands or even hundreds of thousands of them, he enthuses.

The method also holds promise for studying genetic conditions ranging from depression to heart disease. Using stem cells, researchers can culture cells that are genetically identical to a patient known to carry a genetic predisposition to a particular condition, then study how signals move through those cells.

The work was published in Nature Methods on November 28. For more information, please visit http://www.nature.com/nmeth/journal/vaop/ncurrent/full/nmeth.1782.html.

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