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Altered Neuronal Support and Inflammatory Response in Bipolar Disorder Patient-Derived Astrocytes.

  • Author(s): Vadodaria, Krishna C
  • Mendes, Ana PD
  • Mei, Arianna
  • Racha, Vipula
  • Erikson, Galina
  • Shokhirev, Maxim N
  • Oefner, Ruth
  • Heard, Kelly J
  • McCarthy, Michael J
  • Eyler, Lisa
  • Kelsoe, John R
  • Santos, Renata
  • Marchetto, Maria C
  • Gage, Fred H
  • et al.
Abstract

Bipolar disorder (BD) is characterized by cyclical mood shifts. Studies indicate that BD patients have a peripheral pro-inflammatory state and alterations in glial populations in the brain. We utilized an in vitro model to study inflammation-related phenotypes of astrocytes derived from induced pluripotent stem cells (iPSCs) generated from BD patients and healthy controls. BD astrocytes showed changes in transcriptome and induced a reduction in neuronal activity when co-cultured with neurons. IL-1β-stimulated BD astrocytes displayed a unique inflammatory gene expression signature and increased secretion of IL-6. Conditioned medium from stimulated BD astrocytes reduced neuronal activity, and this effect was partially blocked by IL-6 inactivating antibody. Our results suggest that BD astrocytes are functionally less supportive of neuronal excitability and this effect is partially mediated by IL-6. We confirmed higher IL-6 in blood in a distinct cohort of BD patients, highlighting the potential role of astrocyte-mediated inflammatory signaling in BD neuropathology.

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