Blocking a receptor in the brain called mGluR5 is considered a potential strategy for treating a number of disorders, including major depression, Parkinson’s disease and Fragile X Syndrome. Drugs that target the receptor reduce depression-like behaviors in mice, and new research described September 15 in the journal Molecular Psychiatry explains how these compounds exert their effects: they adjust an amplification system in the brain that boosts signaling from certain neurons.

The mGluR5 receptor is one of several molecules found on the surface of neurons that respond to the neurotransmitter glutamate. Researchers are exploring drugs that target mGluR5 and related receptors as an alternative to existing antidepressants, which sometimes cause side effects and are not effective for many patients.

A team of scientists led by Nobel laureate Paul Greengard, Ph.D., a BBRF Scientific Council member and 1992, 2002, and 2008 NARSAD Distinguished Investigator at the Rockefeller University,

wondered whether the antidepressant effects of mGluR5-blocking drugs involved another protein, called p11, that had been found to be involved in depression.

The theory was that p11 might physically interact with mGluR5. The team, which included Dr. Ko-Woon Lee, a research associate in Dr. Greengard's lab who is the first author of the Molecular Psychiatry publication; Dr. Yong Kim, of the same lab; 2009 NARSAD Young Investigator Jodi E. Gresack, Ph.D., and 2006 NARSAD Young Investigator Marc Flajolet, Ph.D., discovered that p11 does indeed interact with the receptor.  It clings to the tail end of the mGluR5 molecule and helps it accumulate at the cell surface, where it can receive signals from outside the cell. The experiments showed that p11 enhances mGluR5 signaling in cells.  

When the team eliminated either mGluR5 or p11 from inhibitory neurons in mice, they saw an antidepressant effect: mice were more likely to explore an open space without exhibiting signs of anxiety. Eliminating mGluR5 or p11 from excitatory cells, however, had the opposite effect. They also found that p11 had to be present for mGluR5-blocking drugs to exert their antidepressant effects.  

The research suggests that drugs that antagonize mGluR5 activity inhibit signaling from a specific class of inhibitory GABAergic neurons. This inhibition of inhibitory cells has the effect of increasing the firing of the excitatory cells they target, called glutamatergic cells. Ultimately, this boosts signaling in the brain and produces the drugs' antidepressant effects, the scientists say.

Read the paper.