Altered astrocytic and microglial homeostasis characterizes a decreased proinflammatory state in bipolar disorder

Abstract

Multiple lines of evidence point to peripheral immune alterations in bipolar disorder (BD) although the activity of brain immune mechanisms remain largely unexplored. To identify the cell type-specific immune alterations in the BD brain, we performed a proteomic and single nuclear transcriptomic analysis ofpostmortemcingulate cortex samples from BD and control subjects. Our results showed that genes associated to the genetic risk for BD are enriched in microglia and astrocytes. Transcriptomic alterations in microglia point to a reduced proinflammatory phenotype, associated to reduced resistance to oxidative stress and apoptosis, which was confirmed with immunohistochemical quantification of IBA1 density. Astrocytes show transcriptomic evidence of an imbalance of multiple metabolic pathways, extracellular matrix composition and downregulated immune signalling. These alterations are associated toADCY2andNCAN,two GWAS genes upregulated in astrocytes. Finally, cell-cell communication analysis prioritized upregulated SPP1-CD44 signalling to astrocytes as a potential regulator of the transcriptomic alterations in BD. Our results indicate that microglia and astrocytes are characterized by downregulated immune responses associated to a dysfunction of core mechanisms via which these cells contribute to brain homeostasis.

Adenylyl cyclase 2 expression and function in neurological diseases

“…This association is also seen in the same pathways in ADHD 87 . Another report finds that Adcy2 is upregulated in both astrocytes and neurons in BD patients 88 . In addition, a missense variant (rs13166360) in Adcy2 is associated with general BD risk, but some polymorphisms are associated with severity of the disease 89 .…”

“… 87 Another report finds that Adcy2 is upregulated in both astrocytes and neurons in BD patients. 88 In addition, a missense variant (rs13166360) in Adcy2 is associated with general BD risk, but some polymorphisms are associated with severity of the disease. 89 For example, Iranian BD patients with the C allele of the rs2290910 polymorphism are more likely to suffer suicidal ideation, and those with the T allele are more likely to attempt suicide.…”