Newswise — A recent study conducted by the Netherlands Institute for Neuroscience reveals that individuals suffering from depression exhibit a reduced count of active microglial cells. What implications does this finding hold?
Depression carries substantial weight in terms of global disease burden and stands as a prominent cause of disability on a global scale. The understanding of its underlying pathophysiology and the development of innovative treatments are crucially necessary, given the prevalence of treatment resistance affecting approximately 30% of patients. Previous investigations have indicated that individuals with depression exhibit disrupted levels of inflammatory markers. Furthermore, depression has been associated with chronic inflammatory conditions like rheumatism, inflammatory bowel disease, and multiple sclerosis. These findings suggest a potential link between brain inflammation and depression. However, further research is needed to ascertain the veracity of this connection.
Karel Scheepstra and his team, under the guidance of Inge Huitinga and Jörg Hamann, conducted a novel study that examined post-mortem brain tissue obtained from individuals who had experienced depression. This brain tissue was generously donated by recently deceased individuals to the Dutch Brain Bank for Psychiatry (NHB-Psy). The study yielded intriguing results: individuals with depression displayed reduced activity in a specific type of immune cells found in the brain, known as microglial cells. Surprisingly, contrary to initial expectations, the observed phenomenon was not one of inflammation but rather a suppression of the immune cells.
Neurons affect microglia
Microglial cells play a crucial role in facilitating efficient communication between neurons by maintaining synapses, the contact points between neurons. Furthermore, these cells continuously monitor the central nervous system for any signs of damaged neurons, synapses, or pathogens. In the case of individuals with depression, the study revealed a noteworthy finding: only microglial cells in proximity to neurons exhibited reduced activity. This led the research team to investigate whether neurons transmit signals to microglial cells during depression, thereby influencing their diminished activity. Remarkably, the investigation confirmed that neurons do indeed send signals to microglial cells, resulting in their decreased activity during depressive episodes.
Karel Scheepstra, a researcher involved in the study and a psychiatrist at Amsterdam UMC, provided insights into the study's methodology and findings. Scheepstra explained that fresh brain tissue obtained immediately after death was utilized to isolate microglial cells, enabling a direct comparison between individuals with depression and control subjects. The observations unveiled abnormal microglial cells in depressed patients, with the most significant irregularities observed in individuals who were highly depressed shortly before their demise. Interestingly, these abnormalities were specifically observed in the gray matter of the brain and not in the white matter. This finding suggests a probable interaction between the microglial cells and the structures present in the gray matter, namely the neurons and synapses.
Furthermore, the study examined the specific nature of these alterations. It had been hypothesized for a considerable period that depression is associated with inflammation in the brain. However, the study's findings presented an intriguing contrast, indicating a different phenomenon: a type of microglia characterized by immune suppression rather than neuroinflammation. These microglial cells were termed "depressed microglia." The researchers delved into understanding how such a phenomenon occurs. They focused on two proteins, CD200 and CD47, present on brain cells and synapses. These proteins engage with microglia and act as a "don't eat me" signal, preventing microglia from engulfing and eliminating damaged connections. Remarkably, the study found elevated levels of these proteins, which contributed to the suppression of microglial activity, potentially impeding the clearance of impaired neural connections.
Neuroplasticity
Depression is believed to be associated with alterations in neuroplasticity, which refers to the brain's ability to form new connections between neurons. Esketamine, a relatively recent antidepressant, targets this process and promotes the growth of new connections. In the present study, the disturbed interaction between neurons and microglial cells was demonstrated. The subsequent phase of research would involve investigating the specific implications of inactive microglia on the maintenance and formation of connections between neurons. Understanding these consequences could shed light on the underlying mechanisms of depression and potentially contribute to the development of novel treatment strategies.
Identifying the specific points of dysfunction in this process holds the potential to serve as targets for the development of new medications. The ability to restore the activity of microglial cells, for instance, raises the question of whether it could have a beneficial effect on the progression of the disease. Currently, the study has successfully demonstrated altered cell activity in the brains of individuals who experienced depression during their lifetime. This enhanced understanding of the underlying issues provides a foundation upon which further research can be built, ultimately paving the way for potential advancements in treatment strategies.
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