Over-Active Glutamate Receptor Gene in Females with Depression

Numerous genes that regulate the activity of a neurotransmitter in the brain have been found to be abundant in brain tissue of depressed females. This could be an underlying cause of the higher incidence of suicide among women, according to research at the University of Illinois at Chicago.

Studying postmortem tissue from brains of psychiatric patients, Monsheel Sodhi, assistant professor of pharmacy practice at UIC, noted that female patients with depression had abnormally high expression levels of many genes that regulate the glutamate system, which is widely distributed in the brain.

Glutamate is the major excitatory neurotransmitter in the brain. Schizophrenia, epilepsy, autism and Alzheimer’s disease have all been linked to abnormalities of the glutamate system.

Gender plays a role in depression and suicide, Sodhi said. Women are two to three times more likely to attempt suicide, but men are four times more likely to die by suicide. The risk of suicide is associated with changes in several neurotransmitter systems.

Sodhi and her colleagues were intrigued by recent studies that found that a low dose of the drug ketamine, which alters glutamate system activity, can rapidly eliminate depression in two-thirds of patients who do not respond to conventional antidepressants. Conventional antidepressants target the monoamine systems, which secrete the neurotransmitters dopamine, serotonin or norepinephrine.

In the new study, published in the journal Molecular Psychiatry, Sodhi and her coworkers analyzed brain tissue from people who had suffered from depression. Both females and males were compared to subjects who had never experienced psychiatric illness. Many of the depressed patients, she said, had died by suicide.

Females with depression, Sodhi discovered, had the highest levels of expression of several glutamate receptor genes, perhaps making them more prone to depression. In addition, three of these genes were found to be elevated in both male and female patients who had died by suicide.

“Our data indicate that females with major depression who are at high risk of suicide may have the greatest antidepressant benefit from drugs that act on the glutamate system, such as ketamine,” Sodhi said. The study also suggests new glutamate receptor targets for development of treatments for depression and identifies biochemical markers that could be used to assess suicide risk, she said.

This is the outline of a woman. Inside here head is an illustration of neurons.

Females with depression had the highest levels of expression of several glutamate receptor genes, perhaps making them more prone to depression. In addition, three of these genes were found to be elevated in both male and female patients who had died by suicide. Image credit: The researchers.

More than 41,000 people die by suicide each year in the United States, according to the Centers for Disease Control and Prevention. It is the second-leading cause of death in people aged 15 to 34 years. Suicide claims a life every 14 minutes in the U.S., and the frequency is escalating. Over 90 percent of the people who take their lives suffer from mental illness, predominantly depression.

Only one-third of patients receiving conventional treatments achieve substantial remission of their depression, which may take several weeks or longer, Sodhi said. This time lag in response to treatment is a problem, she said, due to the high risk of suicide.

About this depression and genetics research

The Sodhi Laboratory, in the UIC department of pharmacy practice, is part of the University of Illinois Depression Center and the Center for Biomolecular Sciences. The research was conducted in collaboration with investigators at the Lieber Institute for Brain Development at Johns Hopkins University, led by Dr. Joel E. Kleinman.

Funding: The study was funded by awards from the American Foundation for Suicide Prevention and the Hans W. Vahlteich Research Fund.

Source: Sam Hostettler – University of Illinois at Chicago
Image Credit: The image is credited to the researchers and is adapted from the University of Illinois at Chicago press release
Original Research: Abstract for “Sex differences in glutamate receptor gene expression in major depression and suicide ” by A L Gray, T M Hyde, A Deep-Soboslay, J E Kleinman and M S Sodhi in Molecular Psychiatry. Published online July 282015 doi:10.1038/mp.2015.91


Abstract

Sex differences in glutamate receptor gene expression in major depression and suicide

Accumulating data indicate that the glutamate system is disrupted in major depressive disorder (MDD), and recent clinical research suggests that ketamine, an antagonist of the N-methyl-d-aspartate (NMDA) glutamate receptor (GluR), has rapid antidepressant efficacy. Here we report findings from gene expression studies of a large cohort of postmortem subjects, including subjects with MDD and controls. Our data reveal higher expression levels of the majority of glutamatergic genes tested in the dorsolateral prefrontal cortex (DLPFC) in MDD (F21,59=2.32, P=0.006). Posthoc data indicate that these gene expression differences occurred mostly in the female subjects. Higher expression levels of GRIN1, GRIN2A-D, GRIA2-4, GRIK1-2, GRM1, GRM4, GRM5 and GRM7 were detected in the female patients with MDD. In contrast, GRM5 expression was lower in male MDD patients relative to male controls. When MDD suicides were compared with MDD non-suicides, GRIN2B, GRIK3 and GRM2 were expressed at higher levels in the suicides. Higher expression levels were detected for several additional genes, but these were not statistically significant after correction for multiple comparisons. In summary, our analyses indicate a generalized disruption of the regulation of the GluRs in the DLPFC of females with MDD, with more specific GluR alterations in the suicides and in the male groups. These data reveal further evidence that, in addition to the NMDA receptor, the AMPA, kainate and the metabotropic GluRs may be targets for the development of rapidly acting antidepressant drugs.

“Sex differences in glutamate receptor gene expression in major depression and suicide ” by A L Gray, T M Hyde, A Deep-Soboslay, J E Kleinman and M S Sodhi in Molecular Psychiatry. Published online July 282015 doi:10.1038/mp.2015.91

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