On the use of animal modeling to study maternal infection during pregnancy and prenatal cytokine exposure as risk factors for schizophrenia

Boksa, Patricia; Luheshi, Giamal N.

doi:10.1016/j.cnr.2003.10.018

Cited by 11 publications

(15 citation statements)

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“…Thus, extrapolation from mouse to man may not be possible on specific days of pregnancy, but can be construed from prenatal and postnatal peaks of neurogenesis, gliogenesis and neuron/glia differentiation and migration (Susser et al 1999). The choice of postnatal days 35 and 56 in our studies are based on a large group of supportive literature (Avishai-Eliner et al 2002;Boksa et al 2003;Kaufmann, 2000;Morgane et al 2002;Romijn et al 1991;Spear, 2000;Susser et al 1999) denoting E0-E10 in rodents as equal to first trimester in humans, E11-E19 as equal to 2 nd trimester, P0-P7 as equal to third trimester (Morgane et al 2002;Stead et al 2006), P35 as equal to adolescence (Spear, 2000) and P56 as equal to early adulthood (Spear, 2000).…”

Section: Animals and Infectionmentioning

confidence: 99%

Viral regulation of aquaporin 4, connexin 43, microcephalin and nucleolin

Fatemi¹,

Folsom²,

Reutiman³

et al. 2008

Schizophrenia Research

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The current study investigated whether human influenza viral infection in midpregnancy leads to alterations in proteins involved in brain development. Human influenza viral infection was administered to E9 pregnant Balb/c mice. Brains of control and virally exposed littermates were subjected to microarray analysis, SDS-PAGE and western blotting at three postnatal stages. Microarray analysis of virally-exposed mouse brains showed significant, two-fold change in expression of multiple genes in both neocortex and cerebellum when compared to sham-infected controls. Levels of mRNA and protein levels of four selected genes were examined in brains of exposed mice. Nucleolin mRNA was significantly decreased in day 0 and day 35 neocortex and significantly increased in day 35 cerebellum. Protein levels were significantly upregulated at days 35 and 56 in neocortex and at day 56 in cerebellum. Connexin 43 protein levels were significantly decreased at day 56 in neocortex. Aquaporin 4 mRNA was significantly decreased in day 0 neocortex. Aquaporin 4 protein levels decreased in neocortex significantly at day 35. Finally, microcephalin mRNA was significantly decreased in day 56 neocortex and protein levels were significantly decreased at 56 cerebellum. These data suggest that influenza viral infection in midpregnancy in mice leads to long term changes in brain markers for enhanced ribosome genesis (nucleolin), increased production of immature neurons (microcephalin), and abnormal glial-neuronal communication (connexin 43 and aquaporin 4).

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Section: Animals and Infectionmentioning

confidence: 99%

Viral regulation of aquaporin 4, connexin 43, microcephalin and nucleolin

Fatemi¹,

Folsom²,

Reutiman³

et al. 2008

Schizophrenia Research

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“…Previous studies have shown that poly(I:C)-induced MIA produces brain and behavioral dysfunctions in the offspring of pregnant rodents [for recent reviews see ref. [2][3][4]. MIA-induced dysfunctions included deficits in prepulse inhibition of acoustic startle [5] , deficits in latent inhibition [6] , and alterations in nucleus accumbens dopaminergic functions [4] .…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, we examined spatial learning and subsequent reversal learning in adolescent offspring using the Morris water maze. Since peripheral cytokine levels may serve as a potential determinant for schizophrenic-like pathological profiles [2,3,9] , we also determined serum levels of TNF-␣ after behavioral testing.…”

Section: Introductionmentioning

confidence: 99%

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Maternal Immune Activation Impairs Reversal Learning and Increases Serum Tumor Necrosis Factor-α in Offspring

Xiao

Li²,

Qi³

et al. 2011

Neuropsychobiology

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Maternal immune activation (MIA) produces a variety of behavioral and brain abnormalities in rodent models of several neuropsychiatric disorders. However, it remains controversial whether MIA impairs reversal learning, a basic function of flexibility relevant to those diseases, in offspring. In the present study, we used the Morris water maze to investigate the effects of middle to late gestation stage poly(I:C) challenges on spatial learning and subsequent reversal learning performance in adolescent rats. Maternal poly(I:C) treatment induced deficits in reversal learning without affecting spatial acquisition abilities. In addition, the serum level of the proinflammatory cytokine tumor necrosis factor-α was increased in MIA rats. This study advances our understanding of how MIA affects adolescent behavior and brain function.

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“…Pharmacological schedules using repeated administration of psychomimetics such as amphetamine, phencyclidine (PCP) and MK-801 have also been widely used (Lillrank et al, 1995;Marcotte et al, 2001;Boksa and Luheshi, 2003;Lipska, 2003;Rung et al, 2005;Amitai et al, 2007;Meyer and Feldon, 2010). These animal models attempt to reflect features of interest to clinical schizophrenia, including sensitivity to drug administration, and behavioural changes in tasks designed to measure traits such as attention, memory and sensorimotor gating (Pratt et al, 2012).…”

Section: Rodent Models Of Schizophreniamentioning

confidence: 99%

Establishing a novel cognitive task in rats of relevance to schizophrenia

Turner¹

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The most debilitating symptoms for patients with neuropsychiatric disorders, such as schizophrenia, are often cognitive deficits; yet they remain largely untreated by current medications. In preclinical animal models, the techniques used to measure cognitive deficits need to be improved to enhance our ability to screen novel drug targets and gain a better understanding of the neurobiological correlates of cognitive dysfunction. Therefore, the aim of this thesis was to develop and test a new high throughput cognitive task in rodents. I have designed a novel Signal Detection Task (SDT) for this purpose.The first aim in developing the SDT was to compare alternative tasks (such as the 5-choice serial reaction time task) and address limitations including the extensive training time required and the lack of control over body position during stimulus presentation.Experiments were then selected to assess the face, construct and predictive validity of the SDT for measuring attentional deficits relevant to schizophrenia. Specifically, I determined if the effects of genetic, environmental, neurobiological and pharmacological manipulations could be detected in rats using this task. The SDT was conducted in rat operant chambers with a series of task variants to probe different components of performance, such as increasing detection difficulty and distraction. Briefly, the studies conducted compared strains (genetics), housing conditions (environment), the impact of a prefrontal cortical lesion (neurobiology) and the effects of amphetamine (pharmacology) on task performance. My findings indicate a relatively short training period was required for rats to perform the SDT with a high level of accuracy compared to other tasks; task acquisition was shown to be dependent on interactions between genetics and environment; prefrontal cortical lesions did not alter baseline performance but impaired attention during distraction and low dose amphetamine significantly improved accuracy. I demonstrated for the first time that the procognitive effects of amphetamine were dependent on baseline attentional performance. In addition, I found that individual variation in baseline performance was related to dopamine metabolism in the striatum.The research outlined in this thesis presents a novel tool for researchers exploring the cognitive phenotype of animal models relevant to neuropsychiatric disorders and for exploring the neurobiology of attention, including mechanisms of action for procognitive medication.ii Declaration by authorThis thesis is composed of my original work, and contains no material previously published or written by another person except where due reference has been made in the text. I have clearly stated the contribution by others to jointly-authored works that I have included in my thesis.

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On the use of animal modeling to study maternal infection during pregnancy and prenatal cytokine exposure as risk factors for schizophrenia

Cited by 11 publications

References 98 publications

Viral regulation of aquaporin 4, connexin 43, microcephalin and nucleolin

Viral regulation of aquaporin 4, connexin 43, microcephalin and nucleolin

Maternal Immune Activation Impairs Reversal Learning and Increases Serum Tumor Necrosis Factor-α in Offspring

Establishing a novel cognitive task in rats of relevance to schizophrenia

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