Therapeutic Targets for Neurodevelopmental Disorders Emerging from Animal Models with Perinatal Immune Activation

Ibi, Daisuke; Yamada, Kiyofumi

doi:10.3390/ijms161226092

Cited by 19 publications

(17 citation statements)

References 128 publications

(174 reference statements)

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“…It is possible that the prenatal microglial perturbations observed here augment astrogenesis or that these signals prime astrocytes, as astrocyte immunomodulation, and transformation into the reactive A1 phenotype, is dependent upon proinflammatory signals released by microglia (94,95). These cells have also been implicated in MIA outside of our model (96,97), and the potential for altered prenatal astrocyte activity in this context presents an important area for future research.…”

Section: Discussionmentioning

confidence: 89%

Maternal viral infection causes global alterations in porcine fetal microglia

Antonson

Lawson

Caputo

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Maternal infections during pregnancy are associated with increased risk of neurodevelopmental disorders, although the precise mechanisms remain to be elucidated. Previously, we established a maternal immune activation (MIA) model using swine, which results in altered social behaviors of piglet offspring. These behavioral abnormalities occurred in the absence of microglia priming. Thus, we examined fetal microglial activity during prenatal development in response to maternal infection with live porcine reproductive and respiratory syndrome virus. Fetuses were obtained by cesarean sections performed 7 and 21 d postinoculation (dpi). MIA fetuses had reduced brain weights at 21 dpi compared to controls. Furthermore, MIA microglia increased expression of major histocompatibility complex class II that was coupled with reduced phagocytic and chemotactic activity compared to controls. High-throughput gene-expression analysis of microglial-enriched genes involved in neurodevelopment, the microglia sensome, and inflammation revealed differential regulation in primary microglia and in whole amygdala tissue. Microglia density was increased in the fetal amygdala at 7 dpi. Our data also reveal widespread sexual dimorphisms in microglial gene expression and demonstrate that the consequences of MIA are sex dependent. Overall, these results indicate that fetal microglia are significantly altered by maternal viral infection, presenting a potential mechanism through which MIA impacts prenatal brain development and function. maternal immune activation | microglia | neurodevelopment | prenatal inflammation | pig Author contributions: A.M.A., M.A.L., and R.W.J. designed research; A.M.A., M.A.L., M.P.C., S.M.M., and B.J.L. performed research; A.M.A., M.P.C., and S.M.M. analyzed data; A.M.A., M.A.L., and R.W.J. interpreted data; and A.M.A. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission.Published under the PNAS license. NEUROSCIENCEDownloaded by guest on July 10, 2020 3 symbols = P < 0.001, 2 symbols = P < 0.01, and 1 symbol = P < 0.05.Antonson et al.

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Section: Discussionmentioning

confidence: 89%

Maternal viral infection causes global alterations in porcine fetal microglia

Antonson

Lawson

Caputo

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…GFAP gene expression was enriched in whole hippocampal tissue, and the relative integrated density of GFAP+ cells was significantly increased in the hilar region. Studies linking astrocytic activity to the etiology of poly I:C-specific MIA [77, 78] highlighted the ability of these glial cells, which express many of the same innate immune receptors as microglia and produce the same cytokines, to respond to MIA insults and participate in neurodevelopmental alterations. MIA models utilizing poly I:C are arguably the most similar to the live viral infection used here, and it is plausible that virally mediated maternal infections follow similar etiologies in the fetal brain.…”

Section: Discussionmentioning

confidence: 99%

Altered Hippocampal Gene Expression and Morphology in Fetal Piglets following Maternal Respiratory Viral Infection

et al. 2018

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Maternal infection during pregnancy increases the risk of neurobehavioral problems in offspring. Evidence from rodent models indicates that the maternal immune response to infection can alter fetal brain development, particularly in the hippocampus. However, information on the effects of maternal viral infection on fetal brain development in gyrencephalic species is limited. Thus, the objective of this study was to assess several effects of maternal viral infection in the last one-third of gestation on hippocampal gene expression and development in fetal piglets. Pregnant gilts were inoculated with porcine reproductive and respiratory syndrome virus (PRRSV) at gestational day (GD) 76 and the fetuses were removed by cesarean section at GD 111 (3 days before anticipated parturition). The gilts infected with PRRSV had elevated plasma interleukin-6 levels and developed transient febrile and anorectic responses lasting approximately 21 days. Despite having a similar overall body weight, fetuses from the PRRSV-infected gilts had a decreased brain weight and altered hippocampal gene expression compared to fetuses from control gilts. Notably, maternal infection caused a reduction in estimated neuronal numbers in the fetal dentate gyrus and subiculum. The number of proliferative Ki-67+ cells was not altered, but the relative integrated density of GFAP+ staining was increased, in addition to an increase in GFAP gene expression, indicating astrocyte-specific gliosis. Maternal viral infection caused an increase in fetal hippocampal gene expression of the inflammatory cytokines TNF-α and IFN-γ and the myelination marker myelin basic protein. MHCII protein, a classic monocyte activation marker, was reduced in microglia, while expression of the MHCII gene was decreased in hippocampal tissue of the fetuses from PRRSV-infected gilts. Together, these data suggest that maternal viral infection at the beginning of the last trimester results in a reduction in fetal hippocampal neurons that is evident 5 weeks after infection, when fetal piglets are near full term. The neuronal reduction was not accompanied by pronounced neuroinflammation at GD 111, indicating that any activation of classic neuroinflammatory pathways by maternal viral infection, if present, is mostly resolved by parturition.

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“…Whilst these iPSC-derived neurons are electrically and synaptically mature when grown under the current conditions, they are still developmentally immature (Livesey et al, 2016). As there is intense interest in the relationship between maternal infection and neurodevelopmental disorders (Cordeiro et al, 2015) and with animal models of prenatal infection being used extensively (Meyer, 2014;Ibi and Yamada, 2015;Reisinger et al, 2015), our observation may offer another mechanism, in addition to the activation of inflammatory pathways, by which viral infections contribute to neurodevelopmental disorders.…”

Section: Tlr3 Activation Impairs Ap Firing In Human Ipsc-derived Neurmentioning

confidence: 94%

Toll-like receptor 3 activation impairs excitability and synaptic activity via TRIF signalling in immature rat and human neurons

et al. 2018

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Toll like receptor 3 (TLR3) belongs to a family of pattern recognition receptors that recognise molecules found on pathogens referred to as pathogen associated molecular patterns (PAMPs). Its involvement in innate immunity is well known but despite its presence in the central nervous system (CNS), our knowledge of its function is limited. Here, we have investigated whether TLR3 activation modulates synaptic activity in primary hippocampal cultures and induced pluripotent stem cell (iPSC)-derived neurons. Synaptically driven spontaneous action potential (AP) firing was significantly reduced by the TLR3 specific activator, poly I:C, in a concentration-dependent manner following both short (5 min) and long exposures (1h) in rat hippocampal cultures. Notably, the consequence of TLR3 activation on neuronal function was reproduced in iPSC-derived cortical neurons, with poly I:C (25 μg/ml, 1h) significantly inhibiting sAP firing. We examined the mechanisms underlying these effects, with poly I:C significantly reducing peak sodium current, an effect dependent on the MyD88-independent TRIF dependent pathway. Furthermore, poly I:C (25 μg/ml, 1h) resulted in a significant reduction in miniature excitatory postsynaptic potential (mEPSC) frequency and amplitude and significantly reduced surface AMPAR expression. These novel findings reveal that TLR3 activation inhibits neuronal excitability and synaptic activity through multiple mechanisms, with this being observed in both rat and human iPSC-derived neurons. These data might provide further insight into how TLR3 activation may contribute to neurodevelopmental disorders following maternal infection and in patients with increased susceptibility to herpes simplex encephalitis.

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Therapeutic Targets for Neurodevelopmental Disorders Emerging from Animal Models with Perinatal Immune Activation

Cited by 19 publications

References 128 publications

Maternal viral infection causes global alterations in porcine fetal microglia

Maternal viral infection causes global alterations in porcine fetal microglia

Altered Hippocampal Gene Expression and Morphology in Fetal Piglets following Maternal Respiratory Viral Infection

Toll-like receptor 3 activation impairs excitability and synaptic activity via TRIF signalling in immature rat and human neurons

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