α7 nicotinic acetylcholine receptor signaling modulates ovine fetal brain astrocytes transcriptome in response to endotoxin: comparison to microglia, implications for prenatal stress and development of 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 {\alpha}7 nicotinic acetylcholine receptor ({\alpha}7nAChR) in fetal astrocytes will augment their neuroprotective transcriptome profile, while the antagonistic stimulation of {\alpha}7nAChR 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 {\alpha}7nAChR agonist or antagonist. Our RNAseq findings show that a pro-inflammatory astrocyte transcriptome phenotype acquired in vitro by LPS stimulation is reversed with {\alpha}7nAChR agonistic stimulation. Conversely, antagonistic {\alpha}7nAChR stimulation potentiates the pro-inflammatory astrocytic transcriptome phenotype. Furthermore, we conduct a secondary transcriptome analysis against the identical {\alpha}7nAChR experiments in fetal sheep primary microglia cultures and against the Simons Simplex Collection for autism spectrum disorder and discuss the implications.
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