GSE123713
a7 nicotinic acetylcholine receptor signaling modulates fetal sheep brain astrocytes transcriptome in response to endotoxin stress: comparison to microglial transcriptome and implications for autism spectrum disorder
Neuroinflammation in utero may result in lifelong neurological disabilities. Astrocytes play a pivotal role, but the mechanisms are poorly understood. No early postnatal treatment strategies exist to enhance neuroprotective potential of astrocytes. We hypothesized that agonism on a7 nicotinic acetylcholine receptor (a7nAChR) in fetal astrocytes will augment their neuroprotective transcriptome profile, while the antagonistic stimulation of a7nAChR will achieve the opposite. Using an in vivo - in vitro model of developmental programming of neuroinflammation induced by lipopolysaccharide (LPS), we validated this hypothesis in primary fetal sheep astrocytes cultures re-exposed to LPS in presence of a selective a7nAChR agonist or antagonist. Our RNAseq findings show that a pro-inflammatory astrocyte phenotype acquired in vitro by LPS stimulation is reversed with a7nAChR agonistic stimulation. Conversely, antagonistic a7nAChR stimulation potentiates the pro-inflammatory astrocytic phenotype. Furthermore, we conduct a secondary transcriptome analysis against the identical a7nAChR experiments in fetal sheep primary microglia cultures and against the Simons Simplex Collection for autism spectrum disorder and discuss the implications. Overall design: Samples from four sheep were used. From each animal we cultured astrocytes, and treated with lipopolysaccharide (LPS), LPS plus AR-R17779 hydrochloride (Tocris Bioscience Cat# 3964), a selective a7nAChR agonist, or LPS plus 100 nM a-Bungarotoxin (Tocris Bioscience Cat# 2133), a selective a7nAChR antagonist, or vehicle (control). There were four replicates for each treatment, except AR-R17779 hydrochloride, for which there were only three.