Cognitive Symptoms Of Mental Disorders May Be Treated By Targeting A Specific Brain Receptor

P. Jeffrey Conn, Ph.D. - Brain & behavior research expert on depression
P. Jeffrey Conn, Ph.D.

A number of psychiatric disorders––schizophrenia, as well as mood disorders like major depression and bipolar disorder––have among their symptoms cognitive deficits, affecting the way people think, including impairments in the ability to pay attention or remember new information. Now, a research team has found evidence of a particular receptor in the brain as a possible target for treating cognitive symptoms.

The research team was led by P. Jeffrey Conn, Ph.D., of Vanderbilt University––a Foundation Scientific Council Member, 1998 recipient of a NARSAD Independent Investigator Grant, and 2004 recipient of a NARSAD Distinguished Investigator Grant. The scientists focused on mGlu3, a cellular docking port for the neurotransmitter glutamate that is important for information processing throughout the brain. Published online January 12th in Proceedings of the National Academy of Sciences, their findings implicate mGlu3 in activity within the prefrontal cortex (PFC), a brain region that coordinates much of our cognition.

Previous research has shown that disrupting the gene that encodes mGlu3 can affect cognition tied to the PFC, and may in fact predispose people to developing disorders linked to altered PFC activity. Examining mouse brains to probe the way mGlu3 influences cognition in the PFC, Dr. Conn and his colleagues found that in the medial (or more central) area of the PFC, mGlu3 controlled the start of a process that helps regulate communication between neurons in the brain. That process is called long-term depression, or LTD. The mice showed reduced LTD when mGlu3 activity was blocked by a chemical agent. And mice with a disrupted mGlu3 gene similarly showed less LTD. This lead to the idea that targeting mGlu3 may be helpful in treating cognitive deficits in people with psychiatric disorders by enabling normal patterns of LTD in the PFC.

The researchers also found that blocking mGlu3 activity interferes with a specific PFC-regulated behavior: fear-extinction learning––that is, learning that something once perceived as a threat no longer signals danger. Since this kind of learning is also associated with activity in the amygdala––part of the brain important for emotional processing and implicated in a number of mood disorders––these findings raise the possibility that mGlu3 helps regulate communication from the amygdala to the PFC and so might affect symptoms of mental illness through this communication channel, as well as through LTD.

The takeaway from this study is that mGlu3 may be a worthwhile new target for alleviating PFC irregularities and their resulting cognitive symptoms, though it is an open question how different PFC functions can be individually targeted for treatment.

Read the abstract.