A receptor for glutamate, the most prominent neurotransmitter in the brain, plays a key role in the process of "unlearning," according to researchers at the Salk Institute for Biological Studies. The finding could eventually help scientists develop new drug therapies for a variety of phobias and anxiety disorders, particularly post-traumatic stress disorder (PTSD). NARSAD Young Investigator Jian Xu, Ph.D., was first author of the study, published in the March 25 issue of the Journal of Neuroscience.
"Most studies focus on 'learning,' but the 'unlearning' process is probably just as important and much less understood," stated Stephen F. Heinemann, Ph.D., a professor in the molecular neurobiology laboratory, who led the research. �Most people agree that failure to 'unlearn' is a hallmark of post-traumatic stress disorders and if we had a drug that affects this gene it could help soldiers coming back from the war to 'unlearn' their fear memories."
PTSD, an anxiety disorder that can develop after exposure to a terrifying event or ordeal, affects approximately 5.2 million Americans, according to the National Institute of Health, including as many as one in eight returning soldiers. If traumatic memories persist inappropriately, sensory cues, sometimes not even recognized consciously, trigger recall of the distressing memories and the associated stress and fear.
As a way of modeling anxiety disorders, researchers train mice to fear a tone by coupling it with a foot shock. If conditioning is followed by repeated exposure to the tone without aversive consequences, the fear will subside, a behavioral change called fear extinction or inhibitory learning.
The Salk researchers were particularly interested in whether metabotropic glutamate receptor 5 (mGluR5), which had been shown to be involved in several forms of behavioral learning, also plays a role in inhibitory learning. Inhibitory learning is thought to be a parallel learning mechanism that requires the acquisition of new information as well as the suppression of previously acquired experiences to be able to adapt to novel situations or environments.
When mice lacking the gene for mGluR5 were put through the fear extinction-drill, they were unable to shake off their fear of the now harmless tone. �We could train the mice to be afraid of the tone but they were unable to erase the association between the tone and the negative experience,� Dr. Xu stated.
In the second series of experiments, Dr. Xu tested whether deleting mGluR5 also affected animals' ability to learn new spatial information. He first trained mice to find a hidden platform placed in a fixed location in the water maze. Although it took mutant mice slightly longer than control animals to remember the position of the submerged platform, they finally learned and were able to find it almost as quickly as the control animals.
Dr. Xu then moved the platform to a different location in the water maze and re-trained the animals. He observed that normal animals quickly adjusted their searching strategy once they realized that the platform had been moved. The mice lacking mGluR5, however, kept returning to the original location. It took them several more trials until they finally gave up searching in the old location.
"Mice without mGluR5 had severe deficits in tasks that required them to 'unlearn' what they had just learned," Dr. Xu explained. "We believe that the same mechanism is perturbed in PTSD, and that mGluR could provide a potential target for therapeutic intervention."