Mouse Study Finds Potential New Drug Target for Depression

Researchers from The Scripps Research Institute (TSRI) are targeting a receptor called GPR158 as a potential contributor to depression after discovering that the protein is elevated in people with major depressive disorder (MDD). To better understand GPR158’s role, the scientists studied male and female mice with and without GPR158 receptors.

The findings suggest that with individuals high levels of GPR158 may be more vulnerable to depression following chronic stress, and the researchers believe they may have discovered a new target for treating major depressive disorder (MDD).

“The next step in this process is to come up with a drug that can target this receptor,” says Kirill Martemyanov, Ph.D., co-chair of the TSRI Department of Neuroscience and senior author of the new study.

The researchers say there is an urgent need for new drug targets in MDD as current pharmacological treatments for depression can take a month to start working — and they don’t work in all patients.

“We need to know what is happening in the brain so that we can develop more efficient therapies,” says Cesare Orlandi, Ph.D., senior research associate at TSRI and co-first author of the study.

During the study, behavioral tests showed that both male and female mice with elevated GPR158 show signs of depression following chronic stress. On the flip side, suppression of the receptor protects mice from developing depressive-like behaviors and makes them resilient to stress.

The researchers found that GPR158 affects key signaling pathways involved in mood regulation in the brain’s prefrontal cortex, though the researchers emphasized that the exact mechanisms remain unknown.

Martemyanov explains that GPR158 is a so-called “orphan receptor” (which gets its name because its binding partner/partners are unknown) with a poorly understood biology and mechanism of action.

GPR158 appears to work downstream from other important brain systems, such as GABA, a major player in the brain’s inhibitory control and adrenergic system involved in stress effects.

“This is really new biology and we still need to learn a lot,” says Martemyanov.

The study also offers a potential clue to why some people are more susceptible to mental illness. Because mice without GPR158 don’t alter their behavior after chronic stress, the researchers concluded these mice were naturally more resilient against depression. Their genetics, or gene expression, offer a layer of protection.

The findings match what doctors have noticed in people who have experienced chronic stress. “There’s always a small population that is resilient — they don’t show the depressive phenotype,” says Laurie Sutton, Ph.D., a research associate at TSRI and co-first author of the study.

As researchers continue to search for new drug targets for depression, they are increasingly using new tools in genome analysis to identify orphan receptors like GPR158.

“Those are the untapped biology of our genomes, with significant potential for development of innovative therapeutics,” says Martemyanov.

The findings are published in the journal eLife.

Source: Scripps Research Institute

Posted by Patricia Adams