A possible serologic biomarker for maternal immune activation-associated neurodevelopmental disorders found in the rat models

AbstractEpidemiological studies have shown that maternal infection during early pregnancy increases the risk of neurodevelopmental disorders (i.e., schizophrenia or autism) in offspring. Recently, diagnostic/stratification biomarkers for the maternal immune activation background in patients with neurodevelopmental disorders have been energetically searched for in the patient blood. Here, we report a novel serologic marker candidate for the disorders found in the maternal immune activation (MIA) rat model. Serum proteome analysis of the MIA rat showed that the immunoglobulin (Ig) light chain is reproducibly augmented. The Ig light chain in sera takes two forms — free form or bound to the Ig heavy chain. Only the former is an inflammatory disease marker, but pro-inflammatory cytokine levels in the sera of the MIA rats were below detectable limits of the ELISA protocol we used. We thereby carried out serum assays of Ig light chains and pro-inflammatory cytokines of commercially available schizophrenia patient sera for research. Although the number of samples was limited, we found augmentation of free Ig light chains but not pro-inflammatory cytokines in sporadic schizophrenia patient sera. Our findings suggest that Ig light chain assay of the schizophrenia/autism patient sera would be worthy to be validated in larger scale

Neuronal dysfunction in cingulate area in maternal immune activation rodent model of schizophrenia.

Schizophrenia is characterized by disturbances of thoughts, perception, cognition and volition. It is reported that about 1% of the world population becomes morbid with schizophrenia. it was reported that D2R ligand binding decreases in the cingulate (Cg) in schizophrenia patients (Suhara et al 2002) by positron emission tomography (PET) study. However, the neuronal pathology of Cg in schizophrenia is not well known. Here we investigated the Cg pathology in maternal immune activation rodent model of schizophrenia by In Vivo and In Vitro analysis. We gave Poly I:C (Sigma P9582: 4mg/kg/day, I.P.) to pregnant rats on gestation days 15-18, which led to increased IL-6, TNF-alpha and IL-1beta but not IL-2 and IL-10 in the maternal serums 3 hours after injection. We then investigated the neuronal function in Cg in mature offspring (12-16 weeks) of the Poly I:C-treated dams (Poly IC rats). Using micro PET, we found that dopamine D2 receptor (D2R) -specific ligand binding potential was significantly decreased in the Cg in Poly IC rats (P<0.003). Abnormal cognitive and/or emotional behavior was observed in these Poly IC rats by behavioral test. The results indicated a high degree of homology between the rodent model of maternal immune activation pathology and schizophrenia patients. Furthermore, we investigated neuronal pathology in the Cg area of the Poly IC rats. The number of Parvalbumin-positive cells (P<0.005) but not NeuN-positive cells was reduced in the Poly IC rats. The D2R exist Parvalbumin-positive interneuron in prefrontal cortex (Khan et al 1998, 2001) . In context, The decreasing number of parvalbumin-positive cell might lead to the reduction of D2R-specific ligand binding potential in the Cg of Poly IC rat. We suggest that number of interneuron might reduce in the Cg in schizophrenia patient arising from maternal immune activation.SFN 201

Maternal immune activation leads to schizophreniform pathology in rodent offspring :Elucidating a non-inherited schizophrenia onset mechanism

Schizophrenia is characterized by disturbances of thoughts, perception, cognition and volition. About 1% of the world population becomes morbid with schizophrenia in adolescence. Recently, emerging literature from epidemiological studies has provided evidence that maternal immune activation contributes to the etiology of schizophrenia. For example, several studies have reported the correlation between influenza infection at pregnancy and increased risk of schizophrenia in offspring. Other maternal infectious diseases such as poliovirus and rubella have also shown correlation with increased risk of schizophrenia, suggesting that not a specific viral infection, but rather maternal immune activation itself appears to be a risk factor of schizophrenia. In animal model studies, maternal immune activation revealed behavioral abnormalities in offspring consistent with observations in schizophrenia. For example, immune activation of pregnant rodents by injection of synthetic polyriboinosinic-polyribocytidilic acid (Poly I:C), which mimics viral infection through Toll-like receptor 3 (TLR3) stimulation, causes their offspring to have reduced the hippocmapal synaptic function, working memory, pre-pulse inhibition and latent inhibition, as well as amphetamine hypersensitivity (Oh-Nishi A 2010, Patterson PH 2009). However, it is unclear whether maternal immune activation produces schizophreniform neuronal pathology in the mature offspring. Recently, using in vivo imaging such as positron emission tomography (PET), dopamine receptor functions were investigated in schizophrenia patients brains, and it was reported that dopamine D2 receptor (D2R) binding decreases in the medial prefrontal cortex (mPFC) (Takahashi et al 2006). Thus, using micro PET, we confirmed that the maternal immune activation rodent model demonstrate D2R binding reduction as in schizophrenia patients. We administered TLR3 ligand synthetic double-stranded RNA Poly I:C, which mimics viral infection causing immune activation, to pregnant rats on gestation days 15-18. This resulted in increased pro-inflammatory cytokines such as IL-6, TNF-alpha and IL-1beta (but not IL-2 and IL-10) in maternal sera 3 hours after Poly I:C injection. We then investigated dopamine receptor function of mature offspring of Poly I:C-treated dams by micro PET with D2/D3R specific ligands such as C11-FLB457. We found that dopamine D2/D3 receptor-specific ligand binding potential was significantly decreased in mPFC in mature offspring of Poly I:C-treated dams (P<0.003) by statistical parametric mapping using PET images, in which the number of Parvalbumin-positive cells (P<0.005) but not NeuN positive cells was reduced. It is suggested that D2R dysfunction might underlie parvalbumin-positive inter-neuronal dysfunction in mPFC of schizophrenia patients (Takahashi et al 2006). In this context, the results indicate a high degree of homology between the rodent model of maternal immune activation pathology and schizophrenia patients. We suggest that maternal increases in pro-inflammatory cytokines might be the pathoetiology of non-inherited schizophrenia.第３２回内藤コンファレン

Neuronal and behavioral pathology in a maternal immune activation rodent model of schizophrenia

Schizophrenia is characterized by disturbances of thoughts, perception, cognition and volition. It is reported that about 1% of the world population becomes morbid with schizophrenia. However, the etiology of schizophrenia is not well known. Recently, it has been suggested that maternal immune activation increases the risk of psychiatric disorders such as schizophrenia in offspring. Here we investigated whether maternal immune activation produces schizophreniform neuronal and behavioral dysfunction in a rat model. We gave double-stranded RNA polyriboinosinic-polyribocytidilic acid (Poly I:C) (0.4mg/kg/day, I.P.) to pregnant rats on gestation days 15-18, which led to increased IL-6, TNF-alpha and IL-1beta but not IL-2 and IL-10 in the maternal serums 3 hours after injection. We then investigated the neuronal and behavioral pathology of mature offspring of the Poly I:C-treated dams. Using positron emission tomography, we found that dopamine D2/D3 receptor-specific ligand binding potential was significantly decreased in the medial prefrontal cortex (mPFC) in mature offspring of Poly I:C-treated dams (P<0.003), and the number of Parvalbumin-positive cells (P<0.005) but not NeuN-positive cells was reduced. Additionally, abnormal cognitive and/or emotional behavior was observed in these mature offspring by open field test. It has been reported that mPFC dysfunction and abnormal cognitive function are typical phenotypes in schizophrenia patients. In this context, the results indicate a high degree of homology between the rodent model of maternal immune activation pathology and schizophrenia patients. We suggest that maternal immune activation might represent convincing pathoetiology of non-inherited schizophrenia.第３４回日本神経科学大

Organization of the marmoset cerebellum in three-dimensional space: lobulation, aldolase C compartmentalization and axonal projection

The cerebellar cortex is organized by transverse foliation and longitudinal compartmentalization. Although the latter, which is recognized through the molecular expression in subsets of Purkinje cells (PCs), is closely related to topographic axonal projection and represents functional divisions, the details have not been fully clarified in mammals other than rodents. Therefore, we examined folial and compartmental organization of the marmoset cerebellum, which resembles the macaque cerebellum, and compared it with that of the rodent cerebellum by aldolase C immunostaining, three-dimensional reconstruction of the PC layer, and labeling of olivocerebellar and corticonuclear projections. Longitudinal stripes of different aldolase C expression intensities separated the entire cerebellar cortex into multiple compartments. Lobule VIIAb-d was equivalent to rodent lobule VIc in that it contained a transverse gap in the cortical layers and served as the rostrocaudal boundary for compartments and axonal branching. Olivocortical and corticonuclear projection patterns in major compartments indicated that the compartmental organization in the marmoset cerebellum was generally equivalent to that in the rodent cerebellum, although two compartments were missing in the pars intermedia and several compartments that have not been seen in rodents were recognized in the flocculus, nodulus, and the most lateral hemisphere. Reconstruction showed that the paraflocculus and flocculus were formed by a single longitudinal sheet, the axis of which was parallel to the aldolase C compartments, PC dendrites, and olivocerebellar climbing fiber distribution. The results indicate that molecular compartmentalization in the marmoset cerebellum reflected both the common fundamental organization of the mammalian cerebellum and species-dependent differentiation

Reduction of dopmamine D2 receptor binding in medial prefrontal cortex in schizophrenia animal model with maternal immune activation

Major Mental disorder such as schizophrenia is characterized by disturbances of thoughts, perception, cognition and volition. It is reported that about 1% of the world population becomes morbid with schizophrenia. However, the schizophrenia pathology and onset mechanism is not well known. Recently, it was reported that dopamine D2 receptor (D2R) binding decreases in medial prefrontal cortex (mPFC) in schizophrenia patient (Suhara T 2002). On the other hands, it has been indicated that maternal immune activation increases the risk of psychiatric disorder such as schizophrenia in offspring. These suggest possibility that maternal immune activation induces to disrupt dopaminergic system, which is then in schizophrenia pathology, in offspring. To test this hypothesis, we gave Toll-like receptor3 ligand synthetic double-stranded RNA polyriboinosinic-polyribocytidilic acid (Poly I:C) (0.4mg/kg/day), which mimic viral infection to cause immune activation, to pregnant rats on gestation days 15-18. And we investigated that D2R ligand (Carbon 11-labeled FLB457) binding potential in whole brain in mature offspring with Poly I:C treated dams, using positron emission tomography. As a result, the Carbon 11-labeled FLB457 binding potential significantly decreased in mPFC in mature offspring with Poly IC treated dams (P< 0.05). This result indicates a high degree of homology between animal model of schizophrenia with maternal immune activation and schizophrenia patient, in disruption of dopaminergic system. We suggest that maternal immune activation might evoke schizophrenia like pathology in adulthoods.第33回日本神経科学大会（Neuro2010