There are drugs in existence that manipulate neurons in the brain for therapeutic effects as well as for studying the functionality of the organ. One issue that has persisted is the lack of specificity of these drugs, as they affect all types of neurons and don’t allow to be selectively targeted toward certain neurons. Now researchers at Duke University and Howard Hughes Medical Institute have created a new technique called DART, that stands for Drugs Acutely Restricted by Tethering, that has allowed them to identify why a certain drug that targets AMPA receptor synaptic proteins failed in a clinical trial.
The technology, just reported in in journal Science, involves genetically modifying target cell types to produce an enzyme on the cells’ surfaces that remains dormant until it meets a drug that has a molecular tag that sticks to the enzyme. The drug ends up accumulating right on the target cells in concentrations orders of magnitude greater than on other types of cells.
Some details of the experiment using the new DART technique:
In an experiment using a mouse model of Parkinson’s disease, [Michael Tadross, assistant professor of biomedical engineering at Duke] and colleagues 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, Tadross 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 said this level of nuance could not have been obtained with prior cell type-specific methods that completely shut neurons down.
Study in journal Science: Deconstructing behavioral neuropharmacology with cellular specificity…