Effects of Two Commonly Found Strains of Influenza A Virus on Developing Dopaminergic Neurons, in Relation to the Pathophysiology of Schizophrenia

Emory University, United States of America
PLoS ONE (Impact Factor: 3.23). 12/2012; 7(12):e51068. DOI: 10.1371/journal.pone.0051068
Source: PubMed


Influenza virus (InfV) infection during pregnancy is a known risk factor for neurodevelopment abnormalities in the offspring, including the risk of schizophrenia, and has been shown to result in an abnormal behavioral phenotype in mice. However, previous reports have concentrated on neuroadapted influenza strains, whereas increased schizophrenia risk is associated with common respiratory InfV. In addition, no specific mechanism has been proposed for the actions of maternal infection on the developing brain that could account for schizophrenia risk. We identified two common isolates from the community with antigenic configurations H3N2 and H1N1 and compared their effects on developing brain with a mouse modified-strain A/WSN/33 specifically on the developing of dopaminergic neurons. We found that H1N1 InfV have high affinity for dopaminergic neurons in vitro, leading to nuclear factor kappa B activation and apoptosis. Furthermore, prenatal infection of mothers with the same strains results in loss of dopaminergic neurons in the offspring, and in an abnormal behavioral phenotype. We propose that the well-known contribution of InfV to risk of schizophrenia during development may involve a similar specific mechanism and discuss evidence from the literature in relation to this hypothesis.

Download full-text


Available from: Gabriel de Erausquin,
  • Source
    • "Interestingly, obstetric complications associated with parkinsonism in schizophrenia (Peralta and Cuesta, 2011) may be influenced by sex (Lane et al., 1996). Midbrain dopamine neurons are known to play a role in the development of sexual dimorphism in the brain and have been shown to be particularly susceptible to environmental insults (De Erausquin et al., 2003; Dorsey et al., 2006; Landreau et al., 2012). Specifically, dopaminergic neurons in the mesocortical projections are more numerous (Kritzer and Creutz, 2008), and have been shown to be more resistant to cytotoxic insults in females than in males (Bourque et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: We tested the hypothesis that loss of substantia nigra neurons in subjects at risk of schizophrenia (1), as reflected by midbrain hyperechogenicity (2) and parkinsonian motor impairment (3), is asymmetric and influenced by sex. We evaluated 62 subjects with never-treated chronic schizophrenia, 80 of their adult, unaffected first degree relatives and 62 healthy controls (matched by sex and age to the cases), part of an Andean population of Northern Argentina. Parkinsonism was scored blindly using UPDRS-3 (Unified Parkinson's Disease Rating Scale) on videotaped exams by 2 independent raters. Transcranial ultrasound was performed by an expert sonographist blind to subject condition with a 2.5MHz transducer through a temporal bone window. Quantification of echogenic area was carried out on saved images by a different evaluator. We found a significant difference in parkinsonian motor impairment between patients, their relatives as well as controls. All three groups showed worse parkinsonism on the left side than the right, corresponding with increased echogenicity on the right substantia nigra compared with the left. Females had significantly more right echogenicity than males, and patients and unaffected relatives were significantly more echogenic than controls on that side. On the left, only female patients had significant echogenicity. Our data supports the notion that unaffected relatives of schizophrenic subjects have increased parkinsonism and concomitant brainstem abnormalities which may represent a vulnerability to the disease. Both motor and brainstem abnormalities are asymmetric and influenced by sex. Copyright © 2015 Elsevier B.V. All rights reserved.
    Schizophrenia Research 02/2015; 164(1-3). DOI:10.1016/j.schres.2015.01.035 · 3.92 Impact Factor
  • Source
    • "As it was mentioned in the introduction, PA is a known risk factor to develop attention deficit hyperactivity disorder (ADHD) and schizophrenia (Cannon et al., 2002; Lewis and Murray, 1987; van Handel et al., 2007). This could be due to the fact that PA produces a dopaminergic system dysregulation (Boksa and El-Khodor, 2003), which in turn has been proposed as one of the neurobiological abnormalities underlying both psychiatric disorders (Del Campo et al., 2011; Howes and Kapur, 2009; Landreau et al., 2012). Moreover, ADHD and schizophrenia are very frequently comorbid with substance abuse (Arias et al., 2008; Gudjonsson et al., 2012; Ringen et al., 2008) and all drugs of abuse cause common effects on the mesolimbic dopamine pathway (Nestler, 2005b). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Perinatal asphyxia (PA) increases the likelihood of suffering from dopamine-related disorders, such as ADHD and schizophrenia. Since dopaminergic transmission plays a major role in cocaine sensitization, the purpose of this study was to determine whether PA could be associated with altered behavioral sensitization to cocaine. To this end, adult rats born vaginally (CTL), by caesarean section (C+), or by C+ with 15 min (PA15, moderate PA) or 19 min (PA19, severe PA) of global anoxia were repeatedly administered with cocaine (i.p., 15 mg/kg) and then challenged with cocaine (i.p., 15 mg/kg) after a five-day withdrawal period. In addition, c-Fos, FosB/ΔFosB, DAT and TH expression were assessed in dorsal (CPu) and ventral (NAcc) striatum. Results indicated that PA15 rats exhibited an increased locomotor sensitization to cocaine, while PA19 rats displayed an abnormal acquisition of locomotor sensitization and did not express a sensitized response to cocaine. c-Fos expression in NAcc, but not in CPu, was associated with these alterations in cocaine sensitization. FosB/ΔFosB expression was increased in all groups and regions after repeated cocaine administration, although it reached lower expression levels in PA19 rats. In CTL, C+ and PA15, but not in PA19 rats, the expression of TH in NAcc was reduced in groups repeatedly treated with cocaine, independently of the challenge test. Furthermore, this reduction was more pronounced in PA15 rats. DAT expression remained unaltered in all groups and regions studied. These results suggest that moderate PA may increase the vulnerability to drug abuse and in particular to cocaine addiction. Synapse, 2013. © 2013 Wiley Periodicals, Inc.
    Synapse 09/2013; DOI:10.1002/syn.21660 · 2.13 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Immunological understanding of neurological and cognitive alterations of schizophrenia has made a significant breakthrough in unfolding the pathophysiological mechanisms of schizophrenia, at least in a group of patients. Such psychoneuroimmunological aberrations essentially argue for an alternative treatment approach based on immunomodulation in schizophrenia. Recent findings in schizophrenia have shown exaggerated immuno-inflammatory responses due to persistent systemic inflammation and neuroinflammation involving microglia activation. The existing antipsychotic drugs have shown substantial benefits in the control of positive symptoms, but they have not demonstrated adequate immuno-dampening effects specifically and effectively. However, a group of emerging nonsteroidal as well as other anti-inflammatory drugs currently being used as an adjunct therapy seem to exhibit increased target specificity and effectiveness in reducing symptom severity to some extent. The anti-inflammatory drugs that have been shown to reduce the levels of pro-inflammatory mediators and inhibit microglia activation have paved the way for better outcomes of schizophrenia treatment. However, many of the currently tested anti-inflammatory drugs often lack methodological robustness. The identification of novel target(s) that will integrate the processes evoked by various risk determinants into a common signalling pathway is urgently required, and this may take immunomodulation into a new therapeutic domain in schizophrenia.
    Current opinion in psychiatry 07/2013; 26(5). DOI:10.1097/YCO.0b013e328363b4da · 3.94 Impact Factor
Show more