Astrocytes derived from patients with bipolar dysfunction

Brain cells called astrocytes derived from induced pluripotent stem cells of patients with bipolar disorder provide suboptimal support for neuronal activity. In an article in the journal Stem Cell Reports, researchers show that this dysfunction can be attributed to an inflammation-promoting molecule called interleukin-6 (IL-6), which is secreted by astrocytes. The results highlight the potential role of astrocyte-mediated inflammatory signaling in psychiatric disease, although more research is needed.

“Our results suggest that IL-6 may contribute to the defects associated with bipolar disorder, opening new avenues for clinical intervention,” said Fred Gage, study co-author of the Salk Institute for Biological Studies.

About 1 to 3% of people have bipolar disorder, which is characterized by recurring mood states ranging from high energy and elation, known as mania, to episodes of low energy and depression. Several data sources suggest a link between unbalanced inflammatory signaling and bipolar disorder. For example, these patients show signs of chronic inflammation and have a higher prevalence of inflammation-related conditions such as cardiovascular disease, diabetes, and metabolic syndrome. Additionally, they have higher concentrations of circulating pro-inflammatory cytokines such as IL-1β and IL-6, especially during manic episodes.

“Although mild inflammation can be beneficial for many neural processes, overproduction of IL-6 can worsen the symptoms of bipolar disorder and may be an important therapeutic target,” said Maria Carolina Marchetto, co-lead author of the study, the Salk Institute and the University. of California San Diego Department of Anthropology.

Astrocytes are known to participate in the inflammatory cascade in the brain. These cells are activated by IL-1β and other pro-inflammatory cytokines and in turn secrete cytokines that participate in the process of neuroinflammation. “Due to a growing understanding of the role of neuroinflammation in psychiatric disorders, we questioned whether the inflammation-induced signaling modification in astrocytes is associated with bipolar disorder,” said Renata Santos, co- lead author of the study, and the Paris Institute of Psychiatry and Neuroscience.

Researchers previously developed a method to rapidly generate inflammation-sensitive astrocytes from human-induced pluripotent stem cells (iPSCs). In the new study, they compared the inflammation signatures in iPSC-derived astrocytes generated by six patients with bipolar disorder and four healthy individuals.

The response of patient astrocytes to pro-inflammatory cytokines revealed a unique transcriptional pattern, characterized by higher expression of the IL-6 gene. As a result, these cells secreted more IL-6, which negatively impacted the activity of co-cultured neurons. Exposure to the astrocyte culture medium was sufficient to decrease neuronal activity, and this effect was partially blocked by the IL-6 inhibiting antibody. In addition, IL-6 blood levels were higher in patients than in healthy individuals.

“These results suggest that factors secreted by astrocytes play a role in the regulation of neuronal activity and that, in the case of bipolar disorder, IL-6 at least in part mediates the effects of astrocytes initiated by the inflammation on neuronal activity, ”said first author Krishna Vadodaria of Salk.

In the future, researchers plan to investigate the effect TheF IL–6 on snowronal avstIvhey. In the meantime, the results should be interpreted with caution. The experiments may not mimic the chronic inflammatory conditions associated with bipolar disorder, and the culture system did not include many cell types involved in potentially relevant immune responses. Additionally, iPSC-derived astrocytes are relatively immature compared to those in the brains of bipolar patients, and there is a lack of reliable biomarkers to determine the exact developmental age.

“At present, extrapolating results directly to patients remains difficult,” said Gage. “Despite these limitations, our results elucidate aspects of the under-studied role of astrocytes in neuroinflammation in psychiatric disorders.”

This research was supported by the Robert and Mary Jane Engman Foundation, Lynn and Edward Streim, the Paul G. Allen Family Foundation, Bob and Mary Jane Engman, the Leona M. and Harry B. Helmsley Charitable Trust, Annette C. Merle- Smith, the G. Harold & Leila Y. Mathers Foundation, the National Institute of Mental Health and the Department of Veterans Affairs.