Age-related changes in neuroinflammation and prepulse inhibition in offspring of rats treated with Poly I:C in early gestation

Abstract

Background Maternal immune activation (MIA) during gestation can increase the later risk of schizophrenia in adult offspring. Neuroinflammation is believed to underlie this process. Postmortem brain studies have found changes in the neuroimmune systems of patients with schizophrenia. However, little is known about the dynamic changes in cerebral inflammation and behavior during the course of the disease. Methods Here, the prepulse inhibition (PPI) test was conducted in adolescent and adult Sprague–Dawley rats prenatally challenged with polyriboinosinic–polyribocytidylic acid (Poly I:C) on gestational day 9 to determine the behavioral trajectory triggered by early exposure to Poly I:C. Brain immune changes were determined in the prefrontal cortex (PFC) and hippocampus (HC) at both ages. The status of the microglia and astrocytes was determined with immunohistochemical staining. The levels of IL-6, IL-1β, and TNF-α in both brain regions were evaluated with enzyme-linked immunosorbent assays. Results Disrupted PPI, the core phenotype of schizophrenia, only emerged in adulthood. Behavioral changes during puberty and adulthood were both accompanied by the activation of microglia (PFC and HC). Astrocytes were only activated at PN60. The levels of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) in the offspring of the Poly I:C-exposed mothers differed with brain region and time, with more cytokines elevated during periadolescence than during adulthood. Conclusions Our findings indicate that immune activation emerged before symptom manifestation in the offspring of MIA rats. We conclude that early prenatal Poly I:C challenge can lead to age-related behavioral and neuroinflammatory changes. These data provide new insight into the neuroinflammatory and neuropathological mechanisms underlying the development of schizophrenia. They also suggest that periadolescence could be more important than adulthood in the prevention and treatment of schizophrenia.

Astroglial Hemichannels and Pannexons: The Hidden Link between Maternal Inflammation and Neurological Disorders

“…Consistent with this, maternal LPS administration accentuates offspring astrogliosis in the hippocampus, cortex, amygdala, hypothalamus, thalamus, and white matter, associated with hypomyelination [87][88][89][90][91]. Likewise, long-lasting astrogliosis takes place in the hippocampus of mice prenatally exposed to the human influenza virus [92], and similar findings have been observed following poly (I:C)-induced maternal immune activation [93][94][95][96]. Despite the latter, other studies have described that prenatal poly (I:C) exposure does not affect the astroglial number and expression of GFAP in the offspring [97][98][99][100].…”

The poly(I:C)-induced maternal immune activation model; a systematic review and meta-analysis of cytokine levels in the offspring

“…(2012) Mice C57BL/6J NR Prenatal (G12.5, G17.5) 5 IV 12.5/17.5 Brain 3–4 IL-6 Corradini et al. (2018) Mice C57BL/6 NR Prenatal(G9 ​+ ​3 ​h, G9 ​+ ​6 ​h, G10)/Post-weaning (P90) 2 IP 9 Brain, whole fetus 4-10 (prenatal), NR (P90) IL-1β, IL-6, IL-17, TGF-β-1, TNF-α Ding et al. (2019) Rats Sprague Dawley M&F Post-weaning (P40, P60) 10 IV 9 Hip, PFC 7–8 IL-1β, IL-6, TNF-α Duchatel et al.…”

Critical Role of the Maternal Immune System in the Pathogenesis of Autism Spectrum Disorder

“…In another investigation, expression of three cytokines, IL-1β, IL-6 and TNF-α, were elevated in the plasma of pregnant rats administrated with Poly I:C, while the effect in the offspring depended on the age and the brain location [105]. In this work, MIA adolescent offspring had significantly higher concentrations of IL-1β and IL-6 than the controls in the prefrontal cortex and hippocampus, while the young adult offspring had significantly elevated levels of TNF-α and IL-6 in the prefrontal cortex despite no significant differences in the hippocampus [105].…”

“…Although a variety of different maternal cytokines have been implicated in ASD [101][102][103]105,106], for the purpose of this literature review, only IL-1β, IL-6 and IL-17 will be discussed, as the pathological mechanisms by which they exert their effects on the prenatal environment are the most well understood.…”