Astrocyte brain cells appear to be functionally less supportive of neuronal activity in people with bipolar disorder, according to a study involving human induced pluripotent stem cells.
The inflammation-promoting molecule interleukin-6 (IL-6), secreted by astrocytes, may contribute to the malfunction, researchers found in the study, published online in the journal Stem Cell Reports.
“While mild inflammation can be beneficial for many neural processes, the overproduction of IL-6 may worsen the symptoms of bipolar disorder and may be an important therapeutic target,” said Maria Carolina Marchetto, PhD, a senior study author from the Salk Institute for Biological Studies and the University of California, San Diego.
When activated by IL-1β and other pro-inflammatory cytokines, astrocytes themselves secrete cytokines involved in neuroinflammation. Researchers wondered whether altered inflammation-driven signaling in the cells played a role in bipolar disorder.
To investigate, they compared inflammation-related phenotypes of astrocytes from induced pluripotent stem cells generated from 6 patients with bipolar disorder and 4 healthy controls.
In patients with bipolar disorder, astrocytes responded to proinflammatory cytokines in a distinct way that was characterized by higher expression of the IL-6 gene. The additional IL-6 secretion reduced neuronal activity, researchers reported. The effect was partially blocked, they added, by using an IL-6 inactivating antibody.
“These results suggest that secreted factors from astrocytes play a role in regulating neuronal activity and that, in the case of bipolar disorder, IL-6 at least in part mediated the effects of inflammation-primed astrocytes on neuronal activity,” said study first author Krishna Vadodaria, PhD, of the Salk Institute.
In a distinct cohort of patients with bipolar disorder, investigators confirmed higher blood levels of IL-6 compared with healthy controls.
“At this moment, direct extrapolation of the results to patients remains challenging," said Fred Gage, PhD, a senior study author from the Salk Institute. “Despite these limitations, our findings elucidate aspects of the understudied role of astrocytes in neuroinflammation in psychiatric disorders.”