Summary: Researchers have identified a new target for the treatment of major depressive disorder.
Source: Scripps Researcher Institute.
Scientists on the Florida campus of The Scripps Research Institute (TSRI) have discovered a new target for treating major depressive disorder, a disease that affects more than 16 million American adults. Their research shows that individuals with high levels of an enigmatic receptor called GPR158 may be more susceptible to depression following chronic stress.
“The next step in this process is to come up with a drug that can target this receptor,” says Kirill Martemyanov, PhD, co-chair of the TSRI Department of Neuroscience and senior author of the new study, published recently in the journal eLife.
The researchers say there is an urgent need for new drug targets in major depressive disorder. 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, PhD, senior research associate at TSRI and co-first author of the study.
The researchers zeroed in on GPR158 as a player in depression after discovering that the protein is elevated in people with major depressive disorder. To better understand GPR158’s role, the scientists studied male and female mice with and without GPR158 receptors.
Behavioral tests revealed that both male and female mice with elevated GPR158 show signs of depression following chronic stress. On the flip side, suppression of GPR158 protects mice from developing depressive-like behaviors and make them resilient to stress.
Next, the researchers examined why GPR158 has these effects on depression. The team demonstrated that GPR158 affects key signaling pathways involved in mood regulation in the region of the brain called prefrontal cortex, though the researchers emphasized that the exact mechanisms remain to be established.
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 the 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.
Laurie Sutton, PhD, a research associate at TSRI and co-first author of the study, says this finding matches 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 Sutton.
As the search goes on for additional targets for depression, Martemyanov says scientists areincreasingly 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,” he says.
Additional authors of the study, “Orphan receptor GPR158 controls stress-induced depression,” were Chenghui Song, Brian S. Muntean, Keqiang Xie, Xiangyang Xie and Baoji Xu of The Scripps Research Institute; Won Chan Oh and Rachel Satterfield of the Max Planck Florida Institute for Neuroscience; Alice Filippini of the University of Brescia; Jazmine D. W. Yaeger and Kenneth J. Renner of the University of South Dakota; Samuel M. Young of the Max Planck Florida Institute for Neuroscience and the University of Iowa; and Hyungbae Kwon of the Max Planck Florida Institute for Neuroscience and the Max Planck Institute of Neurobiology.
Funding: The research was supported by the National Institutes of Health (grants MH105482, HL105550, DA01992, MH107460, 762 DC014093, the University of Iowa, the Max Planck Society and by the Canadian Institutes of Health Research Fellowship.
Source: Stacey Singer DeLoye – Scripps Researcher Institute
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Open access research in eLife.
Orphan receptor GPR158 controls stress-induced depression
Stress can be a motivational force for decisive action and adapting to novel environment; whereas, exposure to chronic stress contributes to the development of depression and anxiety. However, the molecular mechanisms underlying stress-responsive behaviors are not fully understood. Here, we identified the orphan receptor GPR158 as a novel regulator operating in the prefrontal cortex (PFC) that links chronic stress to depression. GPR158 is highly upregulated in the PFC of human subjects with major depressive disorder. Exposure of mice to chronic stress also increased GPR158 protein levels in the PFC in a glucocorticoid-dependent manner. Viral overexpression of GPR158 in the PFC induced depressive-like behaviors. In contrast GPR158 ablation, led to a prominent antidepressant-like phenotype and stress resiliency. We found that GPR158 exerts its effects via modulating synaptic strength altering AMPA receptor activity. Taken together, our findings identify a new player in mood regulation and introduce a pharmacological target for managing depression.