Abstract
BackgroundMaternal 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.MethodsHere, 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.ResultsDisrupted 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.ConclusionsOur 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.
Highlights
Maternal immune activation (MIA) during gestation can increase the later risk of schizophrenia in adult offspring
prepulse inhibition (PPI) test Figure 1 shows the effects of early prenatal polyribocytidylic acid (Poly I):C administration on PPI deficits in the adolescent and adult rat offspring
The adult offspring displayed significant inhibition compared with the control offspring in all the dB groups (72, 74, and 78 dB), whereas the adolescent offspring did not. These results confirm that MIA in the first trimester can induce disrupted PPI after puberty in rats, which is similar to the findings in schizophrenia patients
Summary
Maternal immune activation (MIA) during gestation can increase the later risk of schizophrenia in adult offspring. Little is known about the dynamic changes in cerebral inflammation and behavior during the course of the disease. It has been postulated that the effects on behavior and brain function may depend on the immune responses and factors that mediate these processes, such as cytokines and immune cells, rather than specific pathogens. Researches in animal models of maternal immune activation (MIA) suggest that synthetic viruses or bacterial analogues can lead to behavioral changes related to schizophrenia, further supporting the notion that inflammation is a key player in the pathophysiology of this disorder [7]
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