A new method called DART offers researchers the first opportunity to test what happens when a drug is targeted exclusively to one cell type.
Drugs are the tool of choice for studying the connections between neurons, and continue to be the mainstream treatment for neurological disease. But a major drawback is that the drugs affect all types of neurons, complicating the study of how cell receptors in the synapse—the gap between neurons—work in an intact brain, and how their manipulation can lead to clinical benefits and side effects.
DART (Drugs Acutely Restricted by Tethering) may overcome these limitations. In its inaugural study, scientists were able to see how movement difficulties in a mouse model of Parkinson’s disease are controlled by the AMPA receptor (AMPAR)—a synaptic protein that enables neurons to receive fast incoming signals from other neurons in the brain. The findings reveal why a recent clinical trial of an AMPAR-blocking drug failed, and offer a new approach.
“This study marks a major milestone in behavioral neuropharmacology,” says Michael Tadross, assistant professor of biomedical engineering, who is in the process of moving his laboratory from the HHMI Janelia Research Campus at the Howard Hughes Medical Institute to Duke University. “The insights we gained in studying Parkinson’s mice were unexpected and could not have been obtained with any previous method.”
As reported in Science, DART works by genetically programming a specific cell type to express a sort of GPS beacon. The “beacon” is an enzyme borrowed from bacteria that is inert—it does nothing more than sit on the cell surface. Nothing, that is, until researchers deliver drugs loaded with a special homing device.
Researchers administer these drugs at such low doses that they don’t affect other cells. Because the homing system is so efficient, however, the drug is captured by the tagged cells’ surface, accumulating within minutes to concentrations that are 100 to 1,000 times higher than anywhere else.
In an experiment using a mouse model of Parkinson’s disease, researchers attached the homing signal beacon to two types of neurons found in the basal ganglia—the region of the brain responsible for motor control. One type, referred to as D1 neurons, are believed to give a “go” command. The other, referred to as D2 neurons, are thought to do just the opposite, providing commands to stop movements.
Using DART, researchers delivered an AMPAR-blocking pharmaceutical to only D1-neurons, only D2-neurons, or both. When delivered to both cell types simultaneously, the drugs improved only one of several components of motor dysfunction—mirroring the lackluster results of recent human clinical trials.
The team then found that delivering the drug to only the D1/”go” neurons did absolutely nothing. Surprisingly, however, by targeting the same drug to D2/”stop” neurons, the mice’s movements became more frequent, faster, fluid and linear—in other words, much closer to normal.
While the drug stops neurons from receiving certain incoming signals, it does not completely shut them down. This nuance is particularly important for a subset of the D2 neurons that have two prominent forms of firing. With DART, these components could be separately manipulated, providing the first evidence that Parkinson’s motor deficits are attributable to the AMPAR-based component of firing in these cells. Tadross says this level of nuance was not obtainable with prior cell type-specific methods that completely shut neurons down.
“Already in our first use of DART, we’ve learned something new about the synaptic basis of circuit dysfunction in Parkinson’s disease,” Tadross says. “We’ve discovered that targeting a specific receptor on specific types of neurons can lead to surprisingly potent improvements.”
The Howard Hughes Medical Institute funded the work.
Source: Duke University