Sex-dependent neurobiological features of prenatal immune activation via TLR7.
Journal Article (Journal Article)
Immune activation during pregnancy via infection or autoimmune disease is a risk factor for neuropsychiatric illness. Mouse models of prenatal immune activation often involve maternal administration of agents that activate toll-like receptors (TLRs), a class of pattern recognition receptors that initiate innate immune responses. Such studies have focused primarily on activating the TLR3 or TLR4 subtypes, to mimic immune responses to viral or bacterial infections, respectively. Here, we characterize the effects of prenatal activation of TLR7, which is implicated in the pathogenesis of autoimmune disease. Prenatal TLR7 activation via administration of the selective agonist imiquimod (5.0 mg/kg) induces a phenotype in offspring characterized by reduced anxiety-like behavior, fragmented social behavior, and altered ultrasonic vocalization patterns at 6-12 weeks of age. The characteristics of this phenotype are readily distinguishable from-and in some ways opposite to-those seen following prenatal activation of TLR3 and/or TLR4. Prenatal TLR7-activated mice have normal baseline locomotor activity, but are hyperresponsive to stimuli including social partners, circadian cues, and gonadal hormone fluctuations. These alterations are accompanied by decreases in microglia density but increases in ramifications. RNA-sequencing of dorsal striatum, a region showing profound changes in microglial markers, indicates that prenatal TLR7 activation induces differential expression of hundreds of genes at 13 weeks of age, with virtually no overlap in differentially expressed genes between males and females. Our findings demonstrate that prenatal immune activation can promote a wide range of developmental trajectories, depending on the type and/or pattern of TLR activation and the sex of the offspring.
Full Text
Duke Authors
Cited Authors
- Missig, G; Robbins, JO; Mokler, EL; McCullough, KM; Bilbo, SD; McDougle, CJ; Carlezon, WA
Published Date
- October 2020
Published In
Volume / Issue
- 25 / 10
Start / End Page
- 2330 - 2341
PubMed ID
- 30610201
Pubmed Central ID
- PMC7515834
Electronic International Standard Serial Number (EISSN)
- 1476-5578
International Standard Serial Number (ISSN)
- 1359-4184
Digital Object Identifier (DOI)
- 10.1038/s41380-018-0346-4
Language
- eng