Abstract
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.
Highlights
We discovered that prenatal immune activation selectively targeting TLR7 results in the birth of fewer female offsprings and induces numerous effects on behavior and microglia that are substantially different—and sometimes opposite to—those seen when targeting TLR3 and/or TLR4 [9, 22]
We determined that an underlying feature of the prenatal TLR7 activation phenotype is “conditional hyperresponsiveness,” characterized by exaggerated responses to both exteroceptive and interoceptive stimuli
We demonstrated that prenatal TLR7 activation alters expression of hundreds of genes in manners that are highly dependent on sex, with virtually no overlap between males and females
Summary
Aberrant TLR7 activation may play an important role in the pathogenesis of autoimmunity [16]. In mice, repeated administration of a TLR7 agonist produces systemic autoimmunity, characterized by the presence of anti-nuclear antibodies (ANAs) [17]. Deletion of TLR7 signaling attenuates autoimmune disease progression [18]. Mutations within the TLR7 promoter increase autoimmune disease risk, especially in males [19]. Despite its important role in immune system regulation, the ways in which aberrant TLR7 signaling impacts neurodevelopment is not understood. We used a novel prenatal TLR7 activation regimen, involving administration of a selective TLR7 agonist (imiquimod), to investigate the longterm neurobiological consequences of elevated maternal TLR7 signaling during gestation
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