Did you know that clinical depression causes more years of disability than cancer, HIV/AIDS, and cardiovascular and respiratory diseases combined? A major depressive episode occurs in five to seven percent of the world’s population every year, and one in six people will at some point suffer from the disease.

This is why scientists in Israel and elsewhere are constantly on the search for a better understanding of the biological mechanisms behind depression, which the World Health Organization has deemed “the leading cause of disability worldwide.”

A new study by Hebrew University of Jerusalem scientists, published in the premier psychiatry science journal Molecular Psychiatry in December, was unusual because it focused on a type of brain cell previously overlooked by depression researchers.

Prof. Raz Yirmiya, director of the Hebrew University’s Psychoneuroimmunology Laboratory, and his doctoral student Tirzah Kreisel, together with colleagues in Yirmiya’s lab and at the University of Colorado, showed that changes in one type of non-neuronal brain cells – microglia – play a role in the development of depression following chronic exposure to stress.

Comprising roughly 10% of brain cells, microglia represent the immune system in the brain. However, recent studies have revealed that these cells are also involved in physiological processes not directly related to infection and injury, including the response to stress.

In experiments with animals, the Israeli researchers were able to demonstrate that compounds that alter the functioning of microglia could serve as novel and efficient antidepressant drugs.

Encouraged by the findings, the Hebrew University’s technology transfer company, Yissum, has applied for a patent for the treatment of some forms of depression by several specific microglia-stimulating drugs.

Prof. Raz Yirmiya: “This suggests new avenues for drug research.” Photo courtesy of the Hebrew University

Of mice and microglia

Most research into clinical depression targets the brain’s neuron cells, while the involvement of other types of brain cells has not been thoroughly examined, Yirmiya explained.

Curious about the workings of microglia, the researchers devised an experiment that mimicked chronic unpredictable stress in humans — a leading cause of depression — by exposing mice to repeated, unpredictable stressful conditions over a period of five weeks.

The mice developed behavioral and neurological symptoms mirroring those seen in depressed humans, including a reduction in pleasurable activity and in social interaction, as well as reduced generation of new brain cells (neurogenesis). Decreased neurogenesis is seen an important biological marker of depression.

During the first week of stress exposure, microglia cells actively proliferate and cause the production of specific inflammatory molecules, and then the cells begin to die. Over five weeks of stress exposure, this pattern resulted in a reduction in the number of microglia, and to a degenerated appearance of some microglia cells, particularly in a specific region of the brain involved in stress response.

When the researchers blocked the initial stress-induced activation of microglia with drugs or genetic manipulation, they were able to stop the subsequent microglia cell death and decline, as well as the depressive symptoms and suppressed neurogenesis.

“We were able to demonstrate that such microglia-stimulating drugs served as effective and fast-acting antidepressants, producing complete recovery of the depressive-like behavioral symptoms, as well as increasing the neurogenesis to normal levels within a few days of treatment,” Yirmiya said.

However, these treatments were not effective in mice that had already been exposed to the five-week stress period and therefore had a lower number of microglia at the start of treatment.

Based on these findings, the investigators treated the “depressed” mice with drugs that stimulated the microglia and increased their number to a normal level.

“In addition to the clinical importance of these results, our findings provide the first direct evidence that in addition to neurons, disturbances in the functioning of brain microglia cells have a role in causing psychopathology in general, and depression in particular,” said Yirmiya. “This suggests new avenues for drug research, in which microglia stimulators could serve as fast-acting antidepressants in some forms of depressive and stress-related conditions.”