Unexpected Findings – Depression Associated with Dampened Immune Cells in the Brain

A recent investigation from the Netherlands Institute for Neuroscience links depression with a decrease in microglial cells in the brain. The study paves the way for new potential treatments by highlighting a possible disruption in neuron-microglia communication.

Researchers from the Netherlands Institute for Neuroscience recently discovered that depression is associated with a reduction in brain microglial cells. But what does this mean exactly?

Depression is a major health concern worldwide, contributing significantly to the overall burden of disease. It also ranks high among causes of global disability. Given that nearly a third of patients do not respond to currently available treatments, there is a pressing need to gain a deeper understanding of the disease’s root mechanisms and to develop innovative therapeutic strategies.

Previous research has indicated altered levels of inflammatory markers in patients with depression. Depression is also associated with chronic inflammatory conditions such as rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. These findings suggest a potential role of brain inflammation in depression. But is this accurate?

A team led by Karel Scheepstra, under the guidance of Inge Huitinga and Jörg Hamann, analyzed post-mortem brain tissue from people diagnosed with depression. The brain tissue was obtained from donors who contributed their brains to the Dutch Brain Bank for Psychiatry (NHB-Psy). The findings? A specific immune cell type in our brain, microglial cells, exhibited lower activity in people with depression. This defied expectations, as instead of inflammation, a suppression of immune cells was observed.

Impact of Neurons on Microglia

Microglial cells play a crucial role in the brain as they help maintain connections (synapses) between neurons, facilitating effective communication. Additionally, they continuously monitor the central nervous system for damaged neurons, synapses, and pathogens. In the samples from individuals with depression, only microglial cells close to neurons displayed reduced activity. Consequently, the research team explored whether neurons, during depression, send signals that dampen the activity of microglial cells. Their hypothesis was confirmed.

Image credit: Netherlands Institute for Neuroscience, created with Biorender

Researcher Karel Scheepstra, also a psychiatrist at Amsterdam UMC, stated: “In this study, we isolated microglia from fresh tissue immediately after death and compared these between individuals with depression and controls. We observed abnormal microglia in the depressed patients, with the most pronounced abnormalities in those who were severely depressed before death. Interestingly, abnormalities were exclusively found in the gray matter, not the white matter of the brain. This indicates a likely interaction between microglia and the structures located in the gray matter, namely neurons and synapses.”

“Additionally, we examined the nature of these changes. Despite longstanding hypotheses linking depression with brain inflammation, we are now observing the exact opposite: not neuroinflammation, but an immune-suppressed state of microglia. We coined them as ‘depressed microglia’. We are investigating how this is possible. The proteins CD200 and CD47 found on brain cells and synapses interact with microglia and effectively signal ‘don’t eat me’. We found that these proteins were increased, leading to suppressed microglia, possibly hindering their ability to clear damaged connections.”

Neuroplasticity and Depression

“Depression is often linked with alterations in neuroplasticity, or the ability of neurons to form new connections. Esketamine, a relatively new antidepressant, influences this process and promotes the formation of new connections. In our study, we highlight a disruption in neuron-microglia communication. The next step is to determine the exact implications of inactive microglia on the maintenance and development of neuronal connections.”

“If we can identify where the process goes awry, it could provide targets for new drugs. Can we reactivate these microglia? And what impact would this have on the disease progression? At present, we have established that the brains of individuals who were depressed during life display altered cell activity. This enhances our understanding of the pathologies involved, forming a solid foundation for future work.”

Reference: “Microglia transcriptional profiling in major depressive disorder shows inhibition of cortical grey matter microglia” by Karel W.F. Scheepstra, Mark R. Mizee, Jackelien van Scheppingen, Adelia Adelia, Dennis D. Wever, Matthew R.J. Mason, Marissa L. Dubbelaar, Cheng-Chih Hsiao, Bart J.L. Eggen, Jörg Hamann and Inge Huitinga, 28 April 2023, Biological Psychiatry. DOI: 10.1016/j.biopsych.2023.04.020

I agree to the use of Google Analytics and associated cookies across the TrendMD network (widget, website, blog). Learn more
Yes No

Frequently Asked Questions (FAQs) about Depression and Microglia Activity

More about Depression and Microglia Activity

• Netherlands Institute for Neuroscience
• Dutch Brain Bank for Psychiatry (NHB-Psy)
• Understanding Depression
• Role of Microglia in Brain Function
• Neuroplasticity and Mental Health