Maternal Influenza Viral Infection Causes Schizophrenia-Like Alterations of 5-HT<sub>2A</sub>and mGlu<sub>2</sub>Receptors in the Adult Offspring

Moreno, José L.; Kurita, Mitsumasa; Holloway, Terrell; López, Javier; Cadagan, Richard; Martínez-Sobrido, Luis; Garcı́a-Sastre, Adolfo; González-Maeso, Javier

doi:10.1523/jneurosci.4230-10.2011

Cited by 110 publications

(122 citation statements)

References 85 publications

Supporting

Mentioning

105

Contrasting

Order By: Relevance

“…Here, we combined these two factors, MIA and an acute injection of hallucinogenic drug DOI, and found that MIA offspring display stronger DOI-induced behavioral responses and greater brain activity as measured both by IEG induction and MEMRI. Elevated sensitivity to DOI and up-regulation of egr-1 in the PFC was also reported previously for offspring born to influenzainfected or poly(I:C)-injected pregnant mice (30,31). In addition, these mice also display a decreased density of metabotropic glutamate 2 receptors (mGluR2s) in the PFC.…”

Section: Discussionsupporting

confidence: 76%

“…We and others have previously reported that the MIA mouse model yields offspring with schizophrenia-like behaviors (30,(39)(40)(41)(42)(43). Moreover, another environmental factor that can contribute to the onset of schizophrenia is hallucinogenic drug abuse (3).…”

Section: Discussionmentioning

confidence: 99%

“…Compared with controls, antipsychotic-free human schizophrenic subjects display an increased 5-HT2AR level in the PFC (28). Moreover, rodent models of schizophrenia, including MIA and prenatal or postnatal stress, yield offspring with elevated 5-HT2AR in the PFC, as well as a greater sensitivity to DOI (29)(30)(31). We find that, compared with controls, MIA offspring exhibit a 50% increase in 5-HT2AR mRNA levels in the PFC [t (26) = 2.738, P < 0.05] (Fig.…”

Section: Mia Offspring Have An Increased Level Of 5-ht2ar and Itsmentioning

confidence: 99%

See 2 more Smart Citations

Manganese-enhanced magnetic resonance imaging reveals increased DOI-induced brain activity in a mouse model of schizophrenia

Malkova

Gallagher

et al. 2014

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

View full text Add to dashboard Cite

Significance Here, we model a positive symptom of schizophrenia, hallucination-like activity, in a mouse model of an environmental risk factor of schizophrenia, maternal immune activation (MIA). MIA offspring display an enhanced susceptibility to the hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI) and demonstrate elevated DOI-induced brain activity as measured by induction of immediate early genes and manganese-enhanced MRI. High sensitivity to DOI in MIA offspring can be explained by an increased level of serotonin receptor 2A (5-HT2AR) that mediates the effect of DOI on the prefrontal cortex. Chronic treatment with the 5-HT2AR antagonist ketanserin reduces DOI-induction of head twitching in MIA offspring. Our data demonstrate that DOI-induced hallucination-like activity can be modeled in the MIA mouse model and suggest 5-HT2AR as a potential therapeutic target for schizophrenia.

show abstract

Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Mia Offspring Have An Increased Level Of 5-ht2ar and Itsmentioning

confidence: 99%

See 1 more Smart Citation

Manganese-enhanced magnetic resonance imaging reveals increased DOI-induced brain activity in a mouse model of schizophrenia

Malkova

Gallagher

et al. 2014

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

View full text Add to dashboard Cite

show abstract

“…However, having performed a careful review of the pertinent literature, we found that, in the majority of studies in which neural spread of the A/WSN/33 virus has been shown to occur, this was a result of i.p. infection of pregnant dams (49,50), intranasal infection of immunodeficient mice (23,51), direct intracerebral inoculation (52,53), or infection of suckling mice (54)(55)(56). Indeed, we were able to identify only two studies that described spread to the brain following intranasal administration of influenza A/WSN/33 virus to adult immunocompetent mice, and in both cases, mice were infected using an inoculum 100 or 500 times greater than that used in our studies (57,58).…”

Section: Fig 7 Lung Compliance and Airway Resistance Were Not Alteredmentioning

confidence: 84%

Activation of A ₁ -Adenosine Receptors Promotes Leukocyte Recruitment to the Lung and Attenuates Acute Lung Injury in Mice Infected with Influenza A/WSN/33 (H1N1) Virus

Aeffner

Woods

Davis

2014

J Virol

View full text Add to dashboard Cite

We have shown that bronchoalveolar epithelial A 1 -adenosine receptors (A 1 -AdoR) are activated in influenza A virus-infected mice. Alveolar macrophages and neutrophils also express A 1 -AdoRs, and we hypothesized that activation of A 1 -AdoRs on these cells will promote macrophage and neutrophil chemotaxis and activation and thereby play a role in the pathogenesis of influenza virus-induced acute lung injury. Wild-type (WT) C57BL/6 mice, congenic A 1 -AdoR knockout (A 1 -KO) mice, and mice that had undergone reciprocal bone marrow transfer were inoculated intranasally with 10,000 PFU/mouse influenza A/WSN/33 (H1N1) virus. Alternatively, WT mice underwent daily treatment with the A 1 -AdoR antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) from 1 day prior to inoculation. Infection increased bronchoalveolar lining fluid (BALF) adenosine comparably in WT and A 1 -KO mice. Infection of WT mice resulted in reduced carotid arterial O 2 saturation (hypoxemia), lung pathology, pulmonary edema, reduced lung compliance, increased basal airway resistance, and hyperresponsiveness to methacholine. These effects were absent or significantly attenuated in A 1 -KO mice. Levels of BALF leukocytes, gamma interferon (IFN-␥), and interleukin 10 (IL-10) were significantly reduced in infected A 1 -KO mice, but levels of KC, IP-10, and MCP-1 were increased. Reciprocal bone marrow transfer resulted in WT-like lung injury severity, but BALF leukocyte levels increased only in WT and A 1 -KO mice with WT bone barrow. Hypoxemia, pulmonary edema, and levels of BALF alveolar macrophages, neutrophils, IFN-␥, and IL-10 were reduced in DPCPX-treated WT mice. Levels of viral replication did not differ between mouse strains or treatment groups. These findings indicate that adenosine activation of leukocyte A 1 -AdoRs plays a significant role in their recruitment to the infected lung and contributes to influenza pathogenesis. A 1 -AdoR inhibitor therapy may therefore be beneficial in patients with influenza virus-induced lung injury. IMPORTANCEBecause antiviral drugs are of limited efficacy in patients hospitalized for influenza virus-induced respiratory failure, there is an urgent need for new therapeutics that can limit the progression of lung injury and reduce influenza death rates. We show that influenza A virus infection results in increased production of the nucleoside adenosine in the mouse lung and that activation of A 1 -subtype adenosine receptors by adenosine contributes significantly to both recruitment of innate immune cells to the lung and development of acute lung injury following influenza virus infection. We also show that treatment with an A 1 -adenosine receptor antagonist reduces the severity of lung injury in influenza virus-infected mice. Our findings indicate that adenosine plays an important and previously unrecognized role in the innate immune response to influenza virus infection and suggest that drugs which can inhibit either generation of adenosine or activation of A 1 -adenosine receptors may be beneficia...

show abstract

“…It will be interesting to assess how particular autism-versus schizophrenia-related symptoms, are modulated by changes in timing, intensity and type of MIA [64]. It will also be important to test for endophenotypes that are not shared between these disorders such as repetitive/stereotyped behaviors [21], which are characteristic of autism, and enlarged ventricles [65] and enhanced sensitivity to hallucinogenic drugs [66], which are characteristic of schizophrenia.…”

Section: Immune-related Risk Factors For Asdmentioning

confidence: 99%

Immune Involvement in Autism Spectrum Disorder as a Basis for Animal Models

Hsiao¹

2012

Autism

View full text Add to dashboard Cite

Several of the environmental stimuli suggested to play a role in the pathogenesis of ASD involve altered immune responses during gestation. In this review, we discuss maternal immune activation as a primary risk factor for ASD, with an emphasis on recent findings from animal models of prenatal immune challenges. We further address the presence of autoantibodies as an additional immune-related autism risk factor, drawing upon work done in rodent and monkey models. We then explore the intersection between genetic and environmental susceptibility, with a focus on gene-environment interactions and immune involvement, in genetic risk factors for autism. Finally, we provide emerging evidence for the role of immune dysregulation in the pathogenesis of ASD.

show abstract

Maternal Influenza Viral Infection Causes Schizophrenia-Like Alterations of 5-HT_2Aand mGlu₂Receptors in the Adult Offspring

Abstract: Epidemiological studies indicate that maternal influenza viral infection increases

Cited by 110 publications

References 85 publications

Manganese-enhanced magnetic resonance imaging reveals increased DOI-induced brain activity in a mouse model of schizophrenia

Manganese-enhanced magnetic resonance imaging reveals increased DOI-induced brain activity in a mouse model of schizophrenia

Activation of A ₁ -Adenosine Receptors Promotes Leukocyte Recruitment to the Lung and Attenuates Acute Lung Injury in Mice Infected with Influenza A/WSN/33 (H1N1) Virus

Immune Involvement in Autism Spectrum Disorder as a Basis for Animal Models

Contact Info

Product

Resources

About

Maternal Influenza Viral Infection Causes Schizophrenia-Like Alterations of 5-HT2Aand mGlu2Receptors in the Adult Offspring

Abstract: Epidemiological studies indicate that maternal influenza viral infection increases

Cited by 110 publications

References 85 publications

Manganese-enhanced magnetic resonance imaging reveals increased DOI-induced brain activity in a mouse model of schizophrenia

Manganese-enhanced magnetic resonance imaging reveals increased DOI-induced brain activity in a mouse model of schizophrenia

Activation of A 1 -Adenosine Receptors Promotes Leukocyte Recruitment to the Lung and Attenuates Acute Lung Injury in Mice Infected with Influenza A/WSN/33 (H1N1) Virus

Immune Involvement in Autism Spectrum Disorder as a Basis for Animal Models

Contact Info

Product

Resources

About

Maternal Influenza Viral Infection Causes Schizophrenia-Like Alterations of 5-HT_2Aand mGlu₂Receptors in the Adult Offspring

Activation of A ₁ -Adenosine Receptors Promotes Leukocyte Recruitment to the Lung and Attenuates Acute Lung Injury in Mice Infected with Influenza A/WSN/33 (H1N1) Virus