Title: 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,
Abstract: 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.