Methylazoxymethanol (MAM) treated pregnant rats at gestation day (GD) 17 has revealed itself as a valuable experimental animal model for schizophrenia. Yet, this model remains to be established in mice. In the present study, we examined behavioral, cytoarchitectural, and neurochemical changes in the offspring of MAM treated mice and validated the model’s face, construct and predictive values. We found that in contrast to a single injection of MAM to dams at GD 15, 16 or 17, its repeated administration between GD 15 and 17 led to increase in locomotor activity induced by the NMDA antagonist MK‐801, social withdrawal, short‐term memory impairment and deficit in prepulse inhibition (PPI) in the post‐pubertal offspring. Moreover, we observed a reduction in the volume of both the prefrontal cortex (PFC) and hippocampus, neuroanatomical changes in the hippocampus, and a disturbance in the dopaminergic system in the PFC. In contrast to haloperidol, clozapine, risperidone, and aripiprazole all reversed the PPI deficit in the offspring of MAM treated dams. Therefore, the treatment of pregnant mice with MAM during GD 15‐17 offers a new method to study neurobiological mechanisms involved in the pathogenesis of schizophrenia.

View full abstract

Maternal stress, inflammation, and nutriture during pregnancy are correlated with a higher prevalence of neurodevelopmental disorders, such as autism spectrum disorder (ASD) , attention‐deficit/hyperactivity disorder, and intellectual disability. In the widely used maternal immune activation (MIA) rodent model, the pathology of ASD has been studied. Administration of the viral mimetic, toll‐like receptor (TLR) ligands, such as lipopolysaccharide or polyinosinic‐polycytidylic acid[poly (I : C) ], is commonly used as experimental tools to study neuronal and dysfunctions in ASD. However, a lot of evidence from investigations suggests that these TLR ligands can vary in terms of their immunogenicity in rodent. Here, we will introduce new research findings of the MIA‐induced ASD pathogenesis as well as the problems inducing inflammation by poly (I : C) administration. In addition, we will explain about the usability for a mouse MIA model by gene transfer system continuously expressing proinflammatory cytokine.

View full abstract

The neurodevelopmental hypothesis has been proposed in which impairments of neural cells and networks as a consequence of environmental events occurring in neurodevelopment are involved in the onset of psychiatric disorders during adolescence or early adulthood. Environmental events in neurodevelopment stage produce a variety of inflammatory mediators, whereas the relationship between prostaglandin E₂ (PGE₂) and psychiatric disorders is not clarified. We investigated the possibility of PGE₂ as one of common molecules associated with vulnerability to neurodevelopmental disruptions induced by environmental events. PGE₂ levels in brain were significantly increased after exposure to viral infection, hypoxia, and neglect as neonatal, compared to those after non‐exposure. Mice administered polyriboinosinic‐polycytidylic acid (Poly I : C) or PGE₂ in neonatal exhibited pscychobehavioral and neuronal abnormalities in adult, being attenuated by a PGE₂‐EP1 antagonist. Our findings suggest that PGE₂ is one of potential common molecules associated with vulnerability to neurodevelopmental disruptions induced by environmental events, and PGE₂ plays a crucial role in the development of behavioral and neuronal impairments, which are associated with activation of PGE₂‐EP1. The approaches with such neurodevelopmental model will be invaluable for translational research on novel compounds, and also for providing insight into the pathogenesis and pathophysiology of psychiatric disorders.

View full abstract

Schizophrenia is a severe and common psychiatric disease characterized by hallucinations, delusions, deficit in motivation and cognitive dysfunction. Because many patients show poor or partial response to antipsychotic treatment, it is important to develop novel therapeutic interventions with greater efficacy through new mechanism of action. The hypothesis of inflammation‐induced neurodevelopmental impairment and glutamatergic hypofunction have been proposed as the etiology/pathophysiology of schizophrenia. Kynurenine metabolism is activated by inflammation and there are some metabolites which induce neurotoxicity and affect glutamatergic transmission. Based on the epidemiological hypothesis that maternal gestational exposure to human influenza virus induces vulnerability for the onset of the schizophrenia, embryos of mice are exposed the viral mimic polyriboinosinic‐polyribocytidilic acid (poly I : C) during prenatal period to develop the schizophrenia‐like animal model. In this review, we summarize schizophrenia‐like animal model with neurodevelopmental impairment induced by the prenatal poly I : C exposure and an involvement of kynurenine metabolism in the animal model induced by the prenatal poly I : C exposure. No potential conflicts of interest were disclosed.

View full abstract

Postpartum depression (PPD) of mothers has been suggested to have negative impacts on their children’s development, particularly in terms of development in communicative skills. The authors investigated whether PPD is associated with non‐verbal and verbal communicative skills at the age of 10 months to 3 years and 4 months with the Hamamatsu Birth Cohort Study of Mothers and Children (HBC Study) . Maternal PPD occurring during the first three months postpartum resulted in delay in development of both non‐verbal and verbal communicative skills. The association was statistically significant even after adjusting for known confounders such as breastfeeding status. This finding may provide an important clue to understanding the relationship between maternal PPD and mental health of the children.

View full abstract

Both genetic and environmental factors are involved in the pathophysiology of the major psychiatric disorders including schizophrenia. However, detailed molecular mechanisms are not understood. Brain‐specific somatic mutations including LINE‐1 retrotransposition are found in patients with neuropsychiatric disorders, and their patterns and frequency may play important roles in the pathophysiology of psychiatric disorders. Here we describe molecular mechanism of LINE‐1 retrotransposition and the studies of LINE‐1 retrotransposition using maternal immune activation model in mice.

View full abstract

We have previously reported that dietary deprivation of polyunsaturated fatty acid (PUFA) during neurodevelopmental stages in mice elicited schizophrenia‐like phenotypes in its offspring at adulthood, and that the nuclear receptor peroxisome proliferator‐activated receptor (PPAR) /retinoid X receptor (RXR) system may act as an underlying mechanism linking PUFA deficiency and the behavioral phenotypes. In this study, we further examined whether the PPAR/RXR system is associated with the pathophysiology of schizophrenia. Firstly, we screened for mutations in all the PPAR/RXR genes using the samples of 1,200 Japanese patients with schizophrenia. Based on in silico analyses, we focused on the PPARA gene and its variants (c.209‐2delA, His117Gln, Arg141Cys, and Arg226Trp) that were found exclusively in schizophrenia, but not in control population. The c.209‐2delA variant caused skipping of exon 4, generating a premature termination codon. All the three missense variants decreased the activity of PPARα as a transcription factor in vitro. Next, we examined a Ppara KO mouse model to evaluate the biological consequences evoked by a functional deficiency of this gene in vivo. The Ppara KO mice exhibited behavioral and histological phenotypes that are reminicent of schizophrenia. In conclusion, these findings reinforce the idea that PPARα can be involved in the pathophysiology of schizophrenia.

View full abstract