Summary: Researchers have uncovered a crucial link between depression and the immune system. A new study reveals microglial cells, a type of immune cell in the brain, are less active in individuals with depression.
These findings challenge previous hypotheses suggesting a state of inflammation in the brain associated with depression. Instead, they introduce the concept of suppressed immunity and its potential role in depression, laying the groundwork for future research on potential treatments.
Key Facts:
- Researchers discovered that microglial cells are less active in individuals with depression.
- The suppression of these immune cells was found to occur only in the grey matter of the brain.
- These findings suggest an interaction between microglial cells and neurons, which may influence the formation and maintenance of connections between neurons.
Source: KNAW
People with depression have fewer active microglial cells, according to a new study by the Netherlands Institute for Neuroscience. What does that mean?
Depression is a significant contributor to the global burden of disease and a leading cause of disability worldwide. Insight into disease pathophysiology and novel therapeutics are urgently needed, as treatment resistance is common and occurs in up to 30% of the patients.
Previous research showed that patients with depression have altered levels of inflammatory markers.
In addition, depression has been linked to chronic inflammatory diseases, such as rheumatism, inflammatory bowel disease and multiple sclerosis. These results suggest that inflammation of the brain may play a role in depression. But is that true?
A new study by Karel Scheepstra and his team, supervised by Inge Huitinga and Jörg Hamann, looked at post-mortem human brain tissue from people with depression. This brain tissue comes from recently deceased donors who donated their brains to the Dutch Brain Bank for Psychiatry (NHB-Psy).
And what did they find? A certain type of immune cells in our brain, called microglial cells, are less active in people with depression. Contrary to expectations, the opposite of inflammation actually occurs: the immune cells are suppressed.
Neurons affect microglia
Microglial cells are important because they maintain contact points between neurons (synapses), thereby helping neurons communicate efficiently with each other. In addition, microglial cells constantly scan the central nervous system for damaged neurons, synapses, and pathogens.
In the samples from people with depression, only microglial cells near neurons showed reduced activity. The team therefore investigated whether neurons send signals to the microglial cells during depression, making them less active. And this indeed turned out to be the case.
Karel Scheepstra (researcher involved in the study and also working as a psychiatrist at Amsterdam UMC): “During the study we used fresh tissue immediately after death to isolate microglia and compared these between depressed people and controls. We saw abnormal microglia in depressed patients, with the greatest abnormalities seen in patients who were most depressed just before death.
Interestingly, abnormalities were only seen in the gray matter and not in the white matter of the brain. This suggests that there is a likely interaction between the microglia and the structures located in the gray matter: the neurons and synapses.”
“We also looked at the type of alterations. We’ve hypothesized for years that depression is associated with inflammation of the brain, but we’re now seeing just the opposite: not neuroinflammation, but rather an immune-suppressed type of microglia.
“We termed them ‘depressed microglia’ and we wondered how exactly this is possible. The proteins CD200 and CD47 are located on brain cells and synapses. They interact with microglia and are, as it were, a kind of ‘don’t eat me signal’.
“What we saw is that these proteins were elevated, resulting in suppressed microglia, thereby possibly preventing them from clearing damaged connections.”
Neuroplasticity
“Depression is thought to have something to do with a change in neuroplasticity: the ability to make new connections between neurons. A relatively new antidepressant is esketamine, a drug that intervenes in this process and ensures that more connections start to grow again.
“In this study, we show that there is a disturbed neuron-microglia interaction. The next step would be to see what exactly the consequences of the inactive microglia are for the maintenance and formation of connections between neurons.’
‘If we know where things go wrong in the process, this can provide targets for new medication. Can we make these microglia more active again? And what effect does this have on the course of the disease?
“For now, we have shown that the brains of people who were depressed during life show altered cell activity. This gives us a better understanding of what goes wrong, which we can then build on.”
About this depression research news
Author: Eline Feenstra
Source: KNAW
Contact: Eline Feenstra – KNAW
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Microglia transcriptional profiling in major depressive disorder shows inhibition of cortical grey matter microglia” by Karel Scheepstra et al. Biological Psychiatry
Abstract
Microglia transcriptional profiling in major depressive disorder shows inhibition of cortical grey matter microglia
Background
Microglia have been implicated in the pathophysiology of major depressive disorder (MDD), but information on biological mechanisms is limited. Therefore, we investigated the gene expression profile of microglial cells in relation to neuronal regulators of microglia activity in well-characterized MDD and control autopsy brains.
Methods
Pure, intact microglia were isolated at brain autopsy from occipital cortex grey matter (GM) and corpus callosum white matter (WM) of 13 MDD and 10 age-matched control donors for RNA sequencing. Top differentially expressed genes were validated using immunohistochemistry (IHC) staining. Since gene expression changes were only detected in GM microglia, neuronal regulators of microglia were investigated in cortical tissue and synaptosomes from the cortex by RT-qPCR and Western blot.
Results
Transcriptome analysis revealed 92 genes differentially expressed in microglia isolated from GM, but none in microglia from WM in MDD, compared to controls. Of these, 81 genes were less abundantly expressed in GM MDD, including CD163, MKI67, SPP1, CD14, FCGR1A/C, and C1QA/B/C. Accordingly, pathways related to effector mechanisms, such as the complement system and phagocytosis were differentially regulated in GM microglia in MDD. IHC staining revealed significantly lower expression of CD163 protein in MDD. Whole tissue analysis showed an increase in CD200 (p+0.0009) and CD47 (p=0.068) mRNA, and CD47 protein was significantly elevated (p=0.0396) in synaptic fractions of MDD cases.
Conclusions
Transcriptional profiling indicates an immune-suppressed microglial phenotype in MDD, possibly caused by neuronal regulation.
