Effects of early or late prenatal immune activation in mice on behavioral and neuroanatomical abnormalities relevant to schizophrenia in the adulthood

Abstract

Maternal immune activation (MIA) during pregnancy in rodents increases the risk of the offspring to develop schizophrenia-related behaviors, suggesting a relationship between the immune system and the brain development. Here we tested the hypothesis that MIA induced by the viral mimetic polyinosinic-polycytidylic acid (poly I:C) in early or late gestation of mice leads to behavioral and neuroanatomical disorders in the adulthood. On gestational days (GDs) 9 or 17 pregnant dams were treated with poly I:C or saline via intravenous route and the offspring behaviors were measured during adulthood. Considering the progressive structural neuroanatomical alterations in the brain of individuals with schizophrenia, we used magnetic resonance imaging (MRI) to perform brain morphometric analysis of the offspring aged one year. MIA on GD9 or GD17 led to increased basal locomotor activity, enhanced motor responses to ketamine, a psychotomimetic drug, and reduced time spent in the center of the arena, suggesting an increased anxiety-like behavior. In addition, MIA on GD17 reduced glucose preference in the offspring. None of the treatments altered the relative volume of the lateral ventricles. However, a decrease in brain volume, especially for posterior structures, was observed for one-year-old animals treated with poly I:C compared with control groups. Thus, activation of the maternal immune system at different GDs lead to neuroanatomical and behavioral alterations possibly related to the positive and negative symptoms of schizophrenia. These results provide insights on neuroimmunonological and neurodevelopmental aspects of certain psychopathologies, such as schizophrenia.

Maternal Immune Activation Delays Excitatory-to-Inhibitory Gamma-Aminobutyric Acid Switch in Offspring

“…The use of mouse models based on prenatal immune activation allows for monitoring the impact of the challenge during development and is essential for determining the molecular pathways that mediate the resulting neuropathology (5,7,9). As underlined by Estes and McAllister (4), rodent models of MIA meet all the criteria for a valid disease model because they efficiently mimic a known disease-related risk factor (construct validity), exhibit a range of disease-related symptoms (face validity), and are effectively used to predict the efficacy of treatments (predictive validity).…”

“…In recent years, the consequences of maternal infections on offspring brain have been explored using mouse models based on prenatal exposure to immune stimuli (5)(6)(7)(8)(9). The immunogens most commonly used in rodent models have been lipopolysaccharide, a component of the cell wall of gram-negative bacteria that binds to toll-like receptor 4 and mimics bacterial infection, or polyinosinic:polycytidylic acid (PolyI:C), a doublestranded, synthetic RNA that binds to toll-like receptor 3 like viral nucleic acid.…”

Active HHV-6 Infection of Cerebellar Purkinje Cells in Mood Disorders

“…We studied infection of HHV-6A and HHV-6B by both quantitative PCR-based DNA analysis and immunofluorescence (IFA) assays in post-mortem human cerebellum samples from patients with SCZ, BPD, MDD, and comparison controls (CON). The cerebellum was chosen based on evidence from animal models that perinatal viral infection or immune activation with viral mimetic leads to neuroanatomical changes in the cerebellum, and behavioral disturbances in adulthood ( Williams et al, 2007 ; Shi et al, 2009 ; Aavani et al, 2015 ; da Silveira et al, 2017 ). Furthermore, altered cerebellar function is associated with psychiatric disorders (reviewed in Phillips et al, 2015 ) including abnormal corticocerebellar connections in SCZ ( Ueland et al, 2004 ; Laidi et al, 2015 ), decreased cerebellar volume and cerebellar atrophy in BPD ( Andreasen et al, 1996 ; Baldacara et al, 2011 ) and smaller cerebellum size in MDD patients ( Brambilla et al, 2002 ).…”

Activation of EP2 receptor suppresses poly(I: C) and LPS‐mediated inflammation in primary microglia and organotypic hippocampal slice cultures: Contributing role for MAPKs

“…In addition to the crucial role against infections, several evidences supporting the involvement of the TLR pathways in neuropsychiatric and neurodegenerative diseases exist. For instance, the Poly(I:C) MIA model (maternal immune activation model) represents a valuable approach and has been often shown to induce neuroanatomical abnormalities, schizophrenia, autism and depression‐ like features in adult offspring (Meyer, ; Meyer and Feldon, 2012; Da Silveira et al, ). Systemic challenge in mice with LPS or Poly(I:C) resulted in increased levels of inflammatory cytokines and cyclooxygenase‐2 (COX‐2) in different brain regions.…”